angiogenesis, migration, and invasion [26-29]. During cancer metastasis, dysfunction of RBPs results in the aberrant expression or function of target mRNAs or ncRNAs related to cellular plasticity such as EMT, and affects the malignancy and invasion-related signaling pathways including TGF- $\beta$$\beta$beta\beta, AKT, ERK, WNT, and STAT signals, etc. to promote metastasis [30-34]. In view of this, the development of RBPs-based therapeutic strategy will be helpful and promising for cancer therapy.
血管生成、迁移和侵袭 [26-29]。在癌症转移过程中，RBPs 的功能障碍会导致与细胞可塑性（如 EMT）相关的靶 mRNA 或 ncRNA 表达或功能异常，并影响恶性肿瘤和侵袭相关的信号通路，包括 TGF- $\beta$$\beta$beta\beta 、AKT、ERK、WNT 和 STAT 信号等，从而促进转移 [30-34]。有鉴于此，开发基于 RBPs 的治疗策略将对癌症治疗大有帮助和前景。

In this review, we will focus on the role of RBPs in tumor metastasis, and give an overview about the clinical significance and the underlying mechanisms of RBPs’ dysregulation associated with cancer progression and metastasis.
在这篇综述中，我们将重点讨论 RBPs 在肿瘤转移中的作用，并概述与癌症进展和转移相关的 RBPs 失调的临床意义和潜在机制。

Mounting evidence suggests that abnormal RBP expression and function are connected with cancer metastasis [35,36]. Many RBPs, which are involved in transcriptional control, post-transcriptional regulation, genomic alterations, and post-translational modification (PTM), have been found to be dysregulated in cancer metastasis. Given that the expression, function, and relationship with clinical outcomes of multiple RBPs in human cancers have been widely reported, we summarize the dysregulation and dysfunction of various RBPs associated with metastasis (Table 1), and highlight several well-studied and functionally important RBPs in cancer metastasis.
越来越多的证据表明，RBP 的表达和功能异常与癌症转移有关 [35,36]。许多参与转录调控、转录后调控、基因组改变和翻译后修饰（PTM）的 RBPs 被发现在癌症转移过程中失调。鉴于多种 RBPs 在人类癌症中的表达、功能以及与临床预后的关系已被广泛报道，我们总结了与癌症转移相关的各种 RBPs 的失调和功能障碍（表 1），并重点介绍了几种已被充分研究且在癌症转移中具有重要功能的 RBPs。

Members of the cytoplasmic polyadenylation element binding (CPEB) family are evolutionarily conserved RBPs that are critical regulators of mRNA transport and translation and are implicated in cancer
细胞质多腺苷酸化酶结合（CPEB）家族成员是进化保守的 RBPs，是 mRNA 转运和翻译的关键调控因子，与癌症有关
genesis and progression. There are four members of the CPEB family: CPEB1, CPEB2, CPEB3, and CPEB4. CPEB1 and CPEB3 are identified as tumor suppressors that are down-regulated in a variety of malignancies [34,37-40]. Reduced CPEB1 protein levels have been linked to TGF- $\beta$$\beta$beta\beta-induced EMT and breast cancer metastasis [41], and CPEB3 inhibits EMT and metastasis in hepatocellular carcinoma (HCC) cells [38], indicating that CPEB1 and CPEB3 have an anti-metastatic effect. CPEB4, on the other hand, has been shown to accelerate EMT, migration and invasion of breast cancer cells, and its expression is higher in metastatic breast cancer tissues [42]. In gastric cancer, increased expression of CPEB4 is evidently correlated with metastasis and poor prognosis, attributable to its effects on cell proliferation, migration, and invasion via ZEB1-mediated EMT [43].
的起源和发展。CPEB 家族有四个成员：CPEB1、CPEB2、CPEB3 和 CPEB4。CPEB1 和 CPEB3 被认为是肿瘤抑制因子，在多种恶性肿瘤中被下调 [34,37-40]。CPEB1 蛋白水平的降低与 TGF- $\beta$$\beta$beta\beta 诱导的 EMT 和乳腺癌转移有关 [41]，而 CPEB3 可抑制肝细胞癌（HCC）细胞的 EMT 和转移 [38]，这表明 CPEB1 和 CPEB3 具有抗转移作用。CPEB4 则被证明可加速乳腺癌细胞的 EMT、迁移和侵袭，其在转移性乳腺癌组织中的表达量更高[42]。在胃癌中，CPEB4 的表达增加与转移和预后不良明显相关，这归因于它通过 ZEB1 介导的 EMT 对细胞增殖、迁移和侵袭的影响 [43]。

Epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) are two well-known members of the hnRNP family of RBPs, which are described as epithelial-specific AS modulators that prefer epithelial phenotype. ESRP1 expression is down-regulated in small cell lung cancer, pancreatic ductal adenocarcinoma (PDAC), epithelial ovarian cancer, and lung adenocarcinoma (LUAD) [44-47]. Furthermore, ESRP1 is dysregulated in PDAC and attenuates cell proliferation, migration, invasion, and metastasis via modulating the expression of FGFR-2 isoforms [45]. Intriguingly, an immunohistochemical study of ESRP1 expression in 125 LUAD tissues suggested that ESRP1 overexpression was negatively associated with LUAD patients’ metastases, tumor size, and clinical stage. ESRP1 also represses LUAD cell invasion and metastasis and is involved in the regulation of EMT-associated proteins [47]. On the other hand, there is evidence that ESRP1/2 mRNA expression is
上皮剪接调节蛋白 1 和 2（ESRP1 和 ESRP2）是 hnRNP 家族中两个著名的 RBPs 成员，它们被描述为偏好上皮表型的上皮特异性 AS 调节因子。ESRP1在小细胞肺癌、胰腺导管腺癌（PDAC）、上皮性卵巢癌和肺腺癌（LUAD）中表达下调 [44-47]。此外，ESRP1 在 PDAC 中调控失调，并通过调节 FGFR-2 同工酶的表达减轻细胞增殖、迁移、侵袭和转移 [45]。耐人寻味的是，一项对 125 例 LUAD 组织中 ESRP1 表达的免疫组化研究表明，ESRP1 的过表达与 LUAD 患者的转移、肿瘤大小和临床分期呈负相关。ESRP1 还能抑制 LUAD 细胞的侵袭和转移，并参与 EMT 相关蛋白的调控 [47]。另一方面，有证据表明，ESRP1/2 mRNA 的表达与 LUAD 患者的肿瘤大小和临床分期有关。

Fig. 1. Post-transcriptional regulation of RBPs in cancer metastasis. The synthesis of mRNAs and ncRNAs is accomplished by RNA polymerase II (Pol II). Various RBPs function as regulators of RNA maturity-associated processes, such as AS, alternative polyadenylation, stability, methylation modification, localization, and translation. ncRNAs, primarily miRNAs, lncRNAs, and circRNAs, are processed by RBPs and, in turn, interact with RBPs to influence their function. BioRender (htt ps://biorender.com) was used to create the image.
图 1.癌症转移过程中 RBPs 的转录后调控。mRNA 和 ncRNA 的合成由 RNA 聚合酶 II（Pol II）完成。ncRNA，主要是 miRNA、lncRNA 和 circRNA，由 RBPs 处理，并反过来与 RBPs 相互作用以影响其功能。BioRender (htt ps://biorender.com)用于创建图像。

Table 1  表 1
Targets and dysregulation of RBPs associated with cancer metastasis.
与癌症转移相关的 RBPs 靶点和失调。

Table 1 (continued)  表 1（续）

Abbreviations: alternative splicing (AS); hepatocellular carcinoma (HCC); nasopharyngeal carcinoma (NPC); non-small cell lung cancer (NSCLC); lung adenocarcinoma (LUAD); renal cell carcinoma (RCC); pancreatic ductal adenocarcinoma (PDAC); head and neck squamous cell carcinoma (HNSCC); malignant peripheral nerve sheath tumor (MPNST).
缩写：替代剪接 (AS)；肝细胞癌 (HCC)；鼻咽癌 (NPC)；非小细胞肺癌 (NSCLC)；肺腺癌 (LUAD)；肾细胞癌 (RCC)；胰腺导管腺癌 (PDAC)；头颈部鳞状细胞癌 (HNSCC)；恶性周围神经鞘瘤 (MPNST)。
overexpressed in ovarian cancer cells and tissues, and that ESRP1 may accelerate ovarian cancer progression [48]. The diversity in the cellular environment is likely responsible for ESRP1’s multiple roles in cancer progression.
卵巢癌细胞和组织中过表达，ESRP1 可能会加速卵巢癌的进展 [48]。细胞环境的多样性可能是 ESRP1 在癌症进展中发挥多重作用的原因。

Human Antigen R (HuR), encoded by the ELAVL1 gene, is widely regarded as the best-studied RBP in human cancers. Recent evidence suggests that dysregulation and distribution of HuR may play a role in the invasion and metastasis of many human cancers [49-52]. In breast cancer, HuR expression is increased, and abnormally elevated cytoplasmic HuR is associated with high-grade tumors and a poor prognosis. Targeting the HuR-FOXQ1 relationship may inhibit breast cancer invasion and metastasis [49]. Furthermore, increased HuR mRNA levels were found in ovarian cancer patients, and HuR-mediated stability of long non-coding RNA (lncRNA) NEAT1 promoted tumorigenesis and progression of ovarian cancer [50]. Palomo-Irigoyen et al. recently found that HuR was highly expressed in malignant peripheral nerve sheath tumor (MPNST) samples and may interact with multiple cancer-related transcripts to drive tumor growth and metastasis [51]. Interestingly, HuR and lncRNA HOTAIR are markedly overexpressed in head and neck squamous cell carcinoma (HNSCC) samples, and a positive feedback loop has been established between HuR and lncRNA HOTAIR to promote the progression and metastasis of HNSCC [52].
由 ELAVL1 基因编码的人类抗原 R（HuR）被广泛认为是人类癌症中研究最深入的 RBP。最近的证据表明，HuR 的失调和分布可能在许多人类癌症的侵袭和转移中发挥作用 [49-52]。在乳腺癌中，HuR 表达增加，细胞质中异常升高的 HuR 与高级别肿瘤和不良预后有关。以 HuR-FOXQ1 关系为靶点可抑制乳腺癌的侵袭和转移 [49]。此外，在卵巢癌患者中发现 HuR mNA 水平升高，HuR 介导的长非编码 RNA（lncRNA）NEAT1 的稳定性促进了卵巢癌的肿瘤发生和进展[50]。Palomo-Irigoyen 等人最近发现，HuR 在恶性周围神经鞘瘤（MPNST）样本中高表达，可能与多种癌症相关转录本相互作用，推动肿瘤生长和转移[51]。有趣的是，HuR 和 lncRNA HOTAIR 在头颈部鳞状细胞癌（HNSCC）样本中明显过表达，并且在 HuR 和 lncRNA HOTAIR 之间建立了一个正反馈回路，以促进 HNSCC 的进展和转移 [52]。

Musashi (MSI), a type of neural RBP, was discovered over two decades ago to play a pivotal role in neural development of Drosophila over two decades ago. Currently, only the MSI1 and MSI2 members of
武藏（MSI）是一种神经 RBP，二十多年前被发现在果蝇的神经发育过程中起着关键作用。目前，只有 MSI1 和 MSI2 成员在果蝇的神经发育过程中发挥重要作用。
the human MSI family have been identified, which are evolutionarily conserved and frequently up-regulated in human cancers [53]. Increased MSI1 expression has been linked to invasive breast cancer, lymph node metastatic tissue in colon cancer, and poor outcomes in cervical and gastric cancer [54-57]. Functional studies have consistently shown that silencing of MSI1 suppresses colon cancer cell migration and invasion [55]. MSI1 expression abnormalities can be attributed in part to post-transcriptional regulation, which is mediated by a class of tumor-suppressing miRNAs including miR-128, miR-137, miR-138, and miR-331 [58-60]. MSI2 is up-regulated in highly aggressive non-small cell lung cancer (NSCLC), where it plays an important role in TGF- $\beta$$\beta$beta\beta-induced EMT and drives NSCLC metastasis [61]. MSI2 expression was found to be significantly increased in both PDAC cells and tissues, and was negatively associated with the clinical prognosis of PDAC. Elevated MSI2 expression promotes PDAC cell invasion and metastasis via regulating the Hippo signaling pathway $[62,63]$$[62,63]$[62,63][62,63]. Qu et al. found that conditional deletion of MSI2 in myofibroblasts significantly reduced orthotopically transplanted HCC cell lung metastasis and prolonged overall survival of tumor-bearing mice, suggesting a role for MSI2 in myofibroblasts-mediated HCC invasiveness and metastasis [64].
这些基因在进化上是保守的，而且在人类癌症中经常上调 [53]。MSI1 表达的增加与浸润性乳腺癌、结肠癌淋巴结转移组织以及宫颈癌和胃癌的不良预后有关 [54-57]。功能研究一致表明，沉默 MSI1 可抑制结肠癌细胞的迁移和侵袭 [55]。MSI1 表达异常可部分归因于转录后调控，该调控由一类抑制肿瘤的 miRNA 介导，包括 miR-128、miR-137、miR-138 和 miR-331 [58-60]。MSI2在侵袭性极强的非小细胞肺癌（NSCLC）中上调，在TGF- $\beta$$\beta$beta\beta 诱导的EMT中发挥重要作用，并推动NSCLC转移[61]。研究发现，MSI2在PDAC细胞和组织中的表达均显著增加，并与PDAC的临床预后呈负相关。MSI2表达的升高通过调节Hippo信号通路 $[62,63]$$[62,63]$[62,63][62,63] 促进PDAC细胞的侵袭和转移。Qu等人发现，在肌成纤维细胞中条件性缺失MSI2可显著减少正位移植的HCC细胞肺转移，并延长肿瘤小鼠的总生存期，这表明MSI2在肌成纤维细胞介导的HCC侵袭和转移中发挥作用[64]。

Y-box-binding protein-1 (YB-1) is a well-characterized oncoprotein that acts as both a transcription factor and an RNA-binding protein. It is a member of the superfamily of cold shock proteins. YB-1 is involved in a variety of biological processes, including pre-mRNA splicing, DNA repair, transcription, and translational regulation [65]. Overexpression of YB-1 has been associated with cancer metastasis [66-68]. Wang et al. demonstrated that YB-1 was overexpressed in renal cell carcinoma (RCC) and promoted metastasis via its interaction with G3BP1 [66]. In
Y-盒结合蛋白-1（YB-1）是一种特征明确的肿瘤蛋白，既是转录因子，又是 RNA 结合蛋白。它是冷休克蛋白超家族的成员。YB-1 参与多种生物过程，包括前 mRNA 剪接、DNA 修复、转录和翻译调控 [65]。YB-1 的过表达与癌症转移有关 [66-68]。Wang 等人证实，YB-1 在肾细胞癌（RCC）中过表达，并通过与 G3BP1 的相互作用促进转移 [66]。在

Table 2  表 2
Therapeutics of RBPs associated with cancer metastasis.
治疗与癌症转移相关的 RBPs。

lung adenocarcinoma, YB-1 expression was found to be correlated with differentiation and TNM stage, whereas high YB-1 expression was associated with poorer overall survival (OS). Additionally, by targeting MUC1, YB-1 promotes the stemness and metastasis of lung adenocarcinomas [67]. Zhou et al. discovered that YB-1 expression was increased in nasopharyngeal carcinoma (NPC) tissues and was associated with the T stage and metastasis of NPC patients. Furthermore, they found that overexpression of YB-1 promotes cell migration and invasion in part by regulating the TGF- $\beta$$\beta$beta\beta signaling-induced EMT [68].
研究发现，YB-1的表达与肺腺癌的分化和TNM分期相关，而YB-1的高表达与较差的总生存期（OS）相关。此外，通过靶向 MUC1，YB-1 促进了肺腺癌的干性和转移[67]。Zhou 等人发现，YB-1 在鼻咽癌（NPC）组织中表达增加，并与鼻咽癌患者的 T 期和转移相关。此外，他们还发现 YB-1 的过表达部分通过调节 TGF- $\beta$$\beta$beta\beta 信号诱导的 EMT 促进细胞迁移和侵袭 [68]。

The YTHDF1, YTHDF2, and YTHDF3 are the primary members of the YTH domain protein family, which have been defined as “readers” of N6methyladenosine $\left({\mathrm{m}}^6\mathrm{A}\right)$$\left({\mathrm{m}}^6\mathrm{A}\right)$(m^(6)(A))\left(\mathrm{m}^{6} \mathrm{~A}\right) modification. YTHDF subtypes are mainly distributed in the cytoplasm, and YTHDF1/3 can boost mRNA translation efficiency, whereas YTHDF2 may shorten the half-life of targeted mRNAs. The abnormal expression and function of YTHDF are closely related to the metastasis and prognosis of various human malignant tumors. YTHDF1 is frequently upregulated in ovarian cancer, and patients with high levels of YTHDF1 have a bad prognosis [69]. Wang et al. found that YTHDF1 is upregulated in colorectal cancer (CRC) tissues and promotes CRC metastasis by inhibiting the translation of the RhoA
YTHDF1、YTHDF2和YTHDF3是YTH结构域蛋白家族的主要成员，它们被定义为N6甲基腺苷 $\left({\mathrm{m}}^6\mathrm{A}\right)$$\left({\mathrm{m}}^6\mathrm{A}\right)$(m^(6)(A))\left(\mathrm{m}^{6} \mathrm{~A}\right) 修饰的 "读者"。YTHDF亚型主要分布在细胞质中，YTHDF1/3可提高mRNA的翻译效率，而YTHDF2则可能缩短目标mRNA的半衰期。YTHDF的异常表达和功能与各种人类恶性肿瘤的转移和预后密切相关。YTHDF1在卵巢癌中经常上调，YTHDF1水平高的患者预后较差[69]。Wang 等人发现，YTHDF1 在结直肠癌（CRC）组织中上调，并通过抑制 RhoA 的翻译促进 CRC 的转移。
activator ARHGEF2 [70]. YTHDF3 is abnormally expressed in tumors and plays an important role in metastasis in a similar fashion. Chang et al., for example, discovered that YTHDF3 promotes breast cancer brain metastasis by inducing the translation of ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A}-enriched targets [71]. YTHDF2-depletion promotes the EMT progress of breast cancer cells by increasing translation and protein synthesis rates [72]. However, Zhang et al. reported that YTHDF2 is inversely correlated with HCC patient survival, and revealed that YTHDF2 promotes the cancer stem cell (CSC) phenotype and metastasis of HCC by modulating the ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} methylation of OCT4 mRNA [73].
激活剂 ARHGEF2 [70]。YTHDF3 在肿瘤中异常表达，并以类似的方式在转移中发挥重要作用。例如，Chang 等人发现 YTHDF3 通过诱导 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 富集靶标的翻译促进乳腺癌的脑转移 [71]。YTHDF2-depletion通过增加翻译和蛋白质合成率促进乳腺癌细胞的EMT进展[72]。然而，Zhang 等报道 YTHDF2 与 HCC 患者的生存率成反比，并揭示了 YTHDF2 通过调节 OCT4 mRNA 的 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 甲基化促进 HCC 的癌症干细胞（CSC）表型和转移 [73]。

Furthermore, many other RBPs, such as DEAD-box helicase (DDX) 39B (DDX39B) [74], polypyrimidine tract binding protein 3 (PTBP3) [75], cold shock domain containing E1 (CSDE1) [76-79], and transactivation response element RBP 2 (TARBP2) [80], are abnormally expressed in multiple human cancers and associated with invasion, metastasis, and clinical outcomes. However, RBP dysregulation in cancer metastasis involves not only abnormal expression, but also genetic mutation and alterations in protein activity. For example, HuR mutation can abrogate its binding to phosphorylated UDP-glucose 6-dehydrogenase ( $\mathrm{p}UG\mathrm{DH}$$\mathrm{p}UG\mathrm{DH}$pUGDH\mathrm{p} U G \mathrm{DH} ), relieve the binding of HuR to SNAI1 mRNA, and reduce SNAI1 mRNA stability, thereby inhibiting lung cancer metastasis [81]. Moreover, TARBP2 mutations alter miRNA expression and affect cancer cell proliferation and differentiation [82,83]. Importantly,
此外，许多其他 RBPs，如 DEAD-box 螺旋酶（DDX）39B（DDX39B）[74]、多嘧啶束结合蛋白 3（PTBP3）[75]、含冷休克结构域 E1（CSDE1）[76-79]和反式激活反应元件 RBP 2（TARBP2）[80]，在多种人类癌症中异常表达，并与侵袭、转移和临床结果相关。然而，癌症转移中的 RBP 失调不仅涉及异常表达，还包括基因突变和蛋白活性的改变。例如，HuR突变可使其与磷酸化UDP-葡萄糖6-脱氢酶（ $\mathrm{p}UG\mathrm{DH}$$\mathrm{p}UG\mathrm{DH}$pUGDH\mathrm{p} U G \mathrm{DH} ）的结合失效，解除HuR与SNAI1 mRNA的结合，降低SNAI1 mRNA的稳定性，从而抑制肺癌转移[81]。此外，TARBP2 突变会改变 miRNA 的表达，影响癌细胞的增殖和分化 [82,83]。重要的是
hnRNPE1 may be abnormally activated by TGF $\beta /$$\beta /$beta//\beta / AKT2-mediated phosphorylation at serine 43, eliminating its translational inhibition of target mRNAs encoding critical regulators of EMT and thereby contributing to EMT and metastasis [84,85].
hnRNPE1 可能被 TGF $\beta /$$\beta /$beta//\beta / AKT2 介导的丝氨酸 43 磷酸化异常激活，从而消除了对编码 EMT 关键调控因子的靶 mRNA 的翻译抑制，进而导致 EMT 和转移 [84,85]。

RNA polymerase II synthesizes mRNAs and ncRNAs, and the life of these RNAs is subsequently regulated by their interaction with specific RBPs. In general, most RBPs harbor one or more conventional RBDs, such as the RNA-recognition motif (RRM), hnRNP K-homology (KH) domain, cold-shock domain (CSD), zinc-finger (Znf) domain, doublestrand RNA-binding domain (dsRBD), etc., which allow them to recognize and bind to specific sequence and/or structural motifs in RNA [10]. Moreover, emerging evidence points to an unconventional mechanism of RBP-RNA interaction, in which canonical RBDs are not required for several RBPs to bind to RNA [8]. The structural mechanisms by which several well-characterized RBDs are used to interact with RNA have been expertly reviewed [86]. RBPs interact with RNA to form ribonucleoprotein (RNP) complexes that are involved in several post-transcriptional events, including ncRNA processing, AS, polyadenylation, stability, localization, and translation (Fig. 1). In this section, we will go through the basic mechanisms and targets of various RBPs involved in regulating cancer metastasis (Table 1).
RNA 聚合酶 II 合成 mRNA 和 ncRNA，然后通过与特定 RBPs 的相互作用来调节这些 RNA 的寿命。一般来说，大多数 RBPs 都含有一个或多个传统的 RBD，如 RNA 识别基序（RRM）、hnRNP K-同源结构域（KH）、冷休克结构域（CSD）、锌指（Znf）结构域、双链 RNA 结合结构域（dsRBD）等，这些结构域使它们能够识别 RNA 中的特定序列和/或结构基序并与之结合 [10]。此外，新出现的证据表明，RBP 与 RNA 的相互作用存在一种非常规机制，即一些 RBP 与 RNA 结合并不需要典型的 RBD [8]。已有专家对几种特征明确的 RBD 与 RNA 相互作用的结构机制进行了综述 [86]。RBPs 与 RNA 相互作用形成核糖核蛋白（RNP）复合物，参与多个转录后事件，包括 ncRNA 处理、AS、多腺苷酸化、稳定性、定位和翻译（图 1）。在本节中，我们将介绍参与调控癌症转移的各种 RBPs 的基本机制和靶点（表 1）。

RBPs act as key modulators in the biogenesis and maturation of ncRNAs. Growing evidence suggests that various RBPs are linked to the processing of ncRNAs, including miRNAs, lncRNAs, circRNAs, and splicing small nucleolar RNA (snRNA), which further exert their biological function in cancer at the level of epigenetic regulation or modification. Here, we will focus on the specific RBPs that contribute to ncRNA processing during EMT and cancer metastasis (Fig. 2).
RBPs 是 ncRNAs 生物发生和成熟过程中的关键调节因子。越来越多的证据表明，各种 RBPs 与 ncRNAs（包括 miRNAs、lncRNAs、circRNAs 和剪接小核 RNA (snRNA)）的加工有关，它们在表观遗传调控或修饰水平上进一步发挥其在癌症中的生物学功能。在此，我们将重点研究在 EMT 和癌症转移过程中有助于 ncRNA 处理的特定 RBPs（图 2）。

Dysregulation of miRNA production can have a wide-ranging effect on gene expression and contribute to the development of various human diseases, including cancer. Many miRNAs have been involved in the regulation of the EMT phenotype and metastasis of cancer cells. Multiple reviews are recommended for more functional and mechanistic details of miRNA in metastasis [87-90]. MiRNA biogenesis is tightly controlled both at the transcriptional and post-transcriptional levels. Increasing evidence shows that various RBPs behave as post-transcriptional regulators to affect miRNA mature processes, including the processing of primary miRNAs (pri-miRNAs) to hairpin-precursors (pre-miRNA) by the microprocessor complex in the nucleus, and subsequent miRNA mature processing by DICER in the cytoplasm [91,92]. Here, we will focus on some RBPs that can regulate metastasis-related miRNAs. It is well known that LIN28 plays a role in tumor development and metastasis through inhibiting let-7 processing at the microprocessor and/or DICER levels. Jiang et al. and Wang et al. provide a thorough review of the function of the LIN28/let-7 axis in cancer metastasis [28,93], which is further updated by multiple recent studies [94,95]. In addition to let-7, other miRNAs (miR-9, 107, 143, 200c, 370, and 638) that contain the same tetra-nucleotide sequence motif (GGAG) as pre-let-7 are regulated by LIN28 via the same mechanism [96-99]. Notably, most of these miRNAs have been identified as suppressors of tumor formation and metastasis, suggesting that LIN28 may facilitate cancer metastasis by inhibiting a variety of metastasis-related miRNAs [98-103]. KH-type splicing regulatory protein (KSRP) is a multifunctional RBP that interacts with different miRNA precursors, enabling certain miRNAs to mature [104-106]. There is evidence that KSRP plays a role in the TGF- $\beta$$\beta$beta\beta-mediated EMT process by promoting the maturation of miR-192-5p, which is involved in the targeting of many EMT factors [107]. Additionally, KSRP promotes the maturation of miR-23a, which reduces EGR3 expression by targeting its 3’ untranslated region (UTR) and inhibits NSCLC cell invasion and metastasis [106]. Chromobox
miRNA 生成失调会对基因表达产生广泛影响，并导致包括癌症在内的各种人类疾病的发生。许多 miRNA 参与了癌细胞 EMT 表型和转移的调控。关于 miRNA 在转移中的更多功能和机理细节，推荐阅读多篇综述 [87-90]。MiRNA 的生物发生在转录和转录后水平都受到严格控制。越来越多的证据表明，各种 RBPs 可作为转录后调控因子影响 miRNA 的成熟过程，包括由细胞核中的微处理器复合体将初级 miRNA（pri-miRNA）加工成发夹前体（pre-miRNA），以及随后由细胞质中的 DICER 将 miRNA 加工成熟[91,92]。在此，我们将重点讨论一些可调控转移相关 miRNA 的 RBPs。众所周知，LIN28 通过在微处理器和/或 DICER 水平上抑制 let-7 的加工，在肿瘤发生和转移中发挥作用。Jiang 等人和 Wang 等人全面综述了 LIN28/let-7 轴在癌症转移中的功能[28,93]，最近的多项研究[94,95]进一步更新了这一综述。除了 let-7，其他与 pre-let-7 包含相同四核苷酸序列基序（GGAG）的 miRNA（miR-9、107、143、200c、370 和 638）也通过相同的机制受 LIN28 调节 [96-99]。值得注意的是，这些 miRNA 大多已被确定为肿瘤形成和转移的抑制因子，这表明 LIN28 可能通过抑制多种与转移相关的 miRNA 来促进癌症转移 [98-103]。 KH 型剪接调控蛋白（KSRP）是一种多功能 RBP，可与不同的 miRNA 前体相互作用，使某些 miRNA 成熟[104-106]。有证据表明，KSRP 通过促进 miR-192-5p 的成熟，在 TGF- $\beta$$\beta$beta\beta 介导的 EMT 过程中发挥作用，而 miR-192-5p 参与了许多 EMT 因子的靶向作用 [107]。此外，KSRP 还能促进 miR-23a 的成熟，后者通过靶向 3' 非翻译区（UTR）减少 EGR3 的表达，抑制 NSCLC 细胞的侵袭和转移 [106]。染色体组
protein homolog 8 (CBX8) functions as an oncogene to encourage AKT/ $\beta$$\beta$beta\beta-catenin axis-mediated tumor growth and metastasis by synergistically promoting the transcription of miR-365-3p and EGR1 mRNA [108]. However, CBX8 seems to have a paradoxical effect of promoting proliferation while inhibiting metastasis in esophageal squamous cell carcinoma and colon cancer [109,110]. CBX8 has recently been shown to be involved in the maturation of a variety of pre-miRNAs sharing a consensus sequence [111], implying a post-transcriptional mechanism of the CXB8/miRNA axis in cancer metastasis.
蛋白同源物 8（CBX8）作为一种致癌基因，通过协同促进 miR-365-3p 和 EGR1 mRNA 的转录，促进 AKT/ $\beta$$\beta$beta\beta -catenin 轴介导的肿瘤生长和转移 [108]。然而，CBX8 在食管鳞癌和结肠癌中似乎具有促进增殖同时抑制转移的矛盾效应 [109,110]。最近的研究表明，CBX8 参与了多种具有共识序列的 pre-miRNA 的成熟[111]，这意味着 CXB8/miRNA 轴在癌症转移中的转录后机制。

Additionally, there is growing evidence suggesting that RBPs act as oncogenes or tumor suppressors by modulating lncRNA and circRNA stability and processing. The biosynthesis and post-transcriptional processing of lncRNA and circRNA have received extensive attention [112, 113]. The AS factor Quaking (QKI) has been found to be the primary regulator of circRNA formation during human cell EMT [114]. Chen et al. confirmed that QKI increases circZEB1 levels in prostate cancer cells, and that upregulated circZEB1 further promotes the protein level of the mesenchymal factor ZEB1 by competing with miR-141-3p [115]. HuR was shown in gallbladder cancer to interact with a specific-binding sequence of lncRNA-HGBC to enhance its RNA stability, which further promotes EMT and metastasis of gallbladder cancer cells [116]. Another RBP, eukaryotic initiation factor 4A3 (eIF4A3), interferes with the formation of circRNA-100290 by binding to its flanking sites. The elevated expression of circRNA-100290 is due in part to the low expression of eIF4A3, which contributes to the phenotype of cell proliferation, invasion, and EMT in gastric cancer [117]. In contrast, FUS contributes to circHIF1A biogenesis by interacting with the flanking introns and promotes triple-negative breast cancer (TNBC) cell growth and metastasis [118].
此外，越来越多的证据表明，RBPs 可通过调节 lncRNA 和 circRNA 的稳定性和加工过程来充当致癌因子或肿瘤抑制因子。lncRNA 和 circRNA 的生物合成和转录后处理受到广泛关注 [112，113]。研究发现，AS因子Quaking（QKI）是人体细胞EMT过程中circRNA形成的主要调控因子[114]。Chen 等人证实，QKI 提高了前列腺癌细胞中 circZEB1 的水平，上调的 circZEB1 通过与 miR-141-3p 竞争，进一步促进了间质因子 ZEB1 蛋白水平的提高 [115]。在胆囊癌中，HuR 与 lncRNA-HGBC 的特异性结合序列相互作用，增强其 RNA 稳定性，从而进一步促进胆囊癌细胞的 EMT 和转移 [116]。另一种 RBP--真核启动因子 4A3（eIF4A3）通过与其侧翼位点结合干扰 circRNA-100290 的形成。circRNA-100290的高表达部分是由于eIF4A3的低表达，而eIF4A3有助于胃癌细胞的增殖、侵袭和EMT表型[117]。相反，FUS 通过与侧翼内含子相互作用，促进 circHIF1A 的生物生成，并促进三阴性乳腺癌（TNBC）细胞的生长和转移 [118]。

Importantly, the specific function of RBP frequently necessitates the involvement of ncRNA, and multiple RBPs are engaged in cancer progression and metastasis through directly interacting with ncRNAs [118-124]. Taking circRNA as an example, circNSUN2 serves as a scaffold, forming a complex with RBP IGF2BP2 and HMGA2 mRNA to enhance HMGA2 mRNA stability, promoting colorectal cancer liver metastasis [125].
重要的是，RBP 的特定功能往往需要 ncRNA 的参与，多种 RBP 通过与 ncRNA 直接相互作用参与癌症进展和转移 [118-124]。以 circRNA 为例，circNSUN2 作为支架，与 RBP IGF2BP2 和 HMGA2 mRNA 形成复合物，增强 HMGA2 mRNA 的稳定性，促进结直肠癌肝转移 [125]。

RBP-mediated AS is an important post-transcriptional regulatory mechanism that processes pre-mRNAs to generate distinct mRNA variants from a single gene, contributing to mRNA stability and protein diversity [126-128]. The core spliceosome guides AS events, which include the following main types: constitutive splicing, exon skipping or inclusion, alternative $5^{\prime }$$5^{\prime }$5^(')5^{\prime} or $3^{\prime }$$3^{\prime }$3^(')3^{\prime} splice sites, intron retention, and mutually exclusive exons [129]. Emerging evidence indicates that dysregulation of RBPs (such as AKAP8, DDX39B, hnRNPM, ESRP1, HSRP, and QKI) is implicated in aberrant AS events and AS-associated metastasis, underscoring the crucial function of RBPs-mediated AS in cancer progression [44, 74, 107, 130-133].
RBP 介导的 AS 是一种重要的转录后调控机制，它处理前 mRNA，使单个基因产生不同的 mRNA 变体，从而促进 mRNA 的稳定性和蛋白质的多样性 [126-128]。核心剪接体指导 AS 事件，其中包括以下主要类型：组成型剪接、外显子跳过或包含、替代 $5^{\prime }$$5^{\prime }$5^(')5^{\prime} 或 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} 剪接位点、内含子保留和互斥外显子 [129]。新的证据表明，RBPs（如 AKAP8、DDX39B、hnRNPM、ESRP1、HSRP 和 QKI）的失调与反常 AS 事件和 AS 相关的转移有关，突出了 RBPs 介导的反常 AS 在癌症进展中的关键功能 [44、74、107、130-133]。

It is well known that alternative splicing of CD44 mRNA is associated with EMT and cancer metastasis [130,134]. Multiple RBPs, including ESPR1, hnRNPE1, hnRNPF, hnRNPM, AKAP8, and others, usually interact with each other to regulate CD44 AS-mediated EMT and cancer metastasis [130, 131, 134-137] (Fig. 3). A member of the heterogeneous nuclear ribonucleoprotein (hnRNP) family, hnRNPM, promotes CD44 variable exon skipping to form CD44s isoforms, resulting in a mesenchymal phenotype. However, epithelial splicing regulatory protein 1 (ESRP1) induces CD44 variable exon inclusions to form CD44v isoforms competitively with hnRNPM, promoting an epithelial phenotype of cells [134,138]. According to Harvey et al., the discordant splicing events coregulated by hnRNPM and ESRP1 can be explained by competition for shared GU-rich elements, which are common in genes associated with EMT [139]. In a recent study, A-kinase anchor protein 8 (AKAP8) was found to interact with hnRNPM and antagonize the latter’s splicing activity of CD44. Moreover, AKAP8 can bind to its specific RNA consensus
众所周知，CD44 mRNA 的替代剪接与 EMT 和癌症转移有关 [130,134]。多种 RBPs，包括 ESPR1、hnRNPE1、hnRNPF、hnRNPM、AKAP8 等，通常相互影响，以调控 CD44 AS 介导的 EMT 和癌症转移 [130，131，134-137]（图 3）。异质核核糖核蛋白（hnRNP）家族成员 hnRNPM 可促进 CD44 可变外显子跳过，形成 CD44s 异构体，导致间充质表型。然而，上皮剪接调节蛋白 1（epithelial splicing regulatory protein 1，ESRP1）会诱导 CD44 可变外显子内含形成 CD44v 异构体，与 hnRNPM 竞争，促进细胞上皮表型的形成 [134,138]。根据 Harvey 等人的研究，hnRNPM 和 ESRP1 核心化的不和谐剪接事件可解释为对共享 GU 富含元素的竞争，这些元素在与 EMT 相关的基因中很常见 [139]。最近的一项研究发现，A 激酶锚蛋白 8（AKAP8）与 hnRNPM 相互作用，并拮抗后者对 CD44 的剪接活性。此外，AKAP8 还能与其特定的 RNA 共识结合

Fig. 2. RBPs modulate EMT and cancer metastasis via ncRNA processing and maturation. Upper panel: LIN28 inhibits the expression of several miRNAs that prevent EMT and aggressive metastasis by modulating nucleic processing from pri-miRNA to pre-miRNA as well as cytoplasmic miRNA maturation. KSRP, on the other hand, prefers to regulate pre-miRNA processing in the nucleus in order to trigger metastasis-promoting miRNA expression. Lower panel: RBPs regulate the processing of circRNAs and lncRNAs implicated in EMT and cancer metastasis. BioRender (https://biorender.com) was used to create the image.
图 2.RBPs 通过 ncRNA 的加工和成熟调节 EMT 和癌症转移。上图：LIN28 通过调节从 pri-miRNA 到 pre-miRNA 的核处理以及细胞质 miRNA 的成熟，抑制了几种可防止 EMT 和侵袭性转移的 miRNA 的表达。另一方面，KSRP 更倾向于调节细胞核中的 pre-miRNA 处理，以触发促进转移的 miRNA 表达。下图RBPs 可调控与 EMT 和癌症转移有关的 circRNA 和 lncRNA 的处理。使用 BioRender ( https://biorender.com) 绘制图像。
sequences to inhibit the EMT-associated CLSTN1 exon inclusion, hence preventing breast cancer metastasis [131]. In contrast, mutated MORC2 interacts with hnRNPM and promotes the CD44 splicing switch in lung cancer [132]. Using an in vivo triple-negative model of breast cancer metastasis, RNA sequencing, and specialized bioinformatics analysis, Fish et al. found a novel RNA structural element functioning as a structural splicing enhancer, which is more abundant in the exons of lung metastatic derivative cells compared to parental cells. Moreover, they then identified a protein, SNRPA1, that interacts with the splicing elements to regulate the AS of PLEC, thereby promoting breast cancer cell invasion and metastasis [140] (Fig. 3). In regulating AS, hnRNPs play an important role in the splice-site choice for recognition by the spliceosome. hnRNPA2, a splicing isoform of hnRNPA2/B1, regulates the splicing of A-Raf and then activates the Ras-MAPK-ERK pathway [141]. A recent study has demonstrated that the hnRNPA2 splicing-mediated A-Raf/MAPK axis is involved in the LncRNA-01232-induced metastasis of pancreatic cancer [142] (Fig. 3). ESRP1-mediated AS of specific transcripts, such as CD44 and FGFR2, is involved in the process of EMT and tumor metastasis [45,47]. ESRP1 and ESRP2 are also reduced during EMT and regulate AS events associated with epithelial phenotypes [143,144]. In contrast to ESRP1/2,
序列来抑制与 EMT 相关的 CLSTN1 外显子包涵，从而防止乳腺癌转移 [131]。相反，突变的 MORC2 与 hnRNPM 相互作用，促进了肺癌中 CD44 的剪接转换 [132]。Fish 等人利用体内三阴性乳腺癌转移模型、RNA 测序和专门的生物信息学分析，发现了一种新的 RNA 结构元件，它可作为结构剪接增强子，与亲代细胞相比，这种元件在肺转移衍生细胞的外显子中含量更高。此外，他们还发现了一种蛋白质 SNRPA1，它与剪接元件相互作用，调节 PLEC 的 AS，从而促进乳腺癌细胞的侵袭和转移 [140]（图 3）。hnRNPA2 是 hnRNPA2/B1 的一种剪接异构体，它调控 A-Raf 的剪接，然后激活 Ras-MAPK-ERK 通路[141]。最近的一项研究表明，hnRNPA2 剪接介导的 A-Raf/MAPK 轴参与了 LncRNA-01232- 诱导的胰腺癌转移[142]（图 3）。ESRP1 介导的特定转录本（如 CD44 和 FGFR2）的 AS 参与了 EMT 和肿瘤转移过程 [45,47]。ESRP1 和 ESRP2 在 EMT 过程中也会减少，并调节与上皮表型相关的 AS 事件 [143,144]。与 ESRP1/2 不同的是，ESRP2 和 ESRP1

QKI-5 is upregulated during EMT and drives widespread EMT-associated AS programs in breast cancer cells as a target of miR-200c/375 [133]. However, recent studies have demonstrated that QKI inhibits EMT in oral squamous cell carcinoma as well as TGF- $\beta$$\beta$beta\beta-induced EMT in NSCLC cells [30,145]. DDX39B belongs to the DEAD box (DDX) RNA helicase family. It is a pivotal splicing factor and is highly expressed in colorectal cancer, promoting EMT and metastasis. Mechanistically, DDX39B directly binds to the FUT3 precursor mRNA and promotes its splicing, thereby upregulating FUT3 expression (Fig. 3). Increased expression of FUT3 activates the TGF- $\beta$$\beta$beta\beta signaling pathway by hastening the fucosylation of type I TGF $\beta$$\beta$beta\beta receptor (TGF $\beta$$\beta$beta\beta RI) [74]. In addition to its role in miRNA processing, KSRP may regulate AS events of a set of precursor mRNAs, including CD44 and FGFR2, in order to undermine TGF- $\beta$$\beta$beta\beta-induced EMT [107]. Recent evidence suggests that polypyrimidine tract-binding protein 3 (PTBP3) performs as a metastatic-promoting factor by multiple post-transcriptional roles such as AS, mRNA stability, and translation activation in various cancer types [75, 146-148]. PTBP3 was reported to carry out its AS role by binding to the CU-rich region of CAV1 intron to reduce the expression of the CAV1 $\alpha$$\alpha$alpha\alpha isoform, which suppressed the migration and invasion of gastric cancer cells in vitro, as well as lymph node metastasis in vivo [75].
作为 miR-200c/375 的靶标，QKI-5 在 EMT 过程中上调，并驱动乳腺癌细胞中广泛的 EMT 相关 AS 程序 [133]。然而，最近的研究表明，QKI 可抑制口腔鳞状细胞癌的 EMT 以及 TGF- $\beta$$\beta$beta\beta 诱导的 NSCLC 细胞的 EMT [30,145]。DDX39B 属于 DEAD box（DDX）RNA 螺旋酶家族。它是一个关键的剪接因子，在结直肠癌中高表达，可促进 EMT 和转移。从机制上讲，DDX39B 直接与 FUT3 前体 mRNA 结合并促进其剪接，从而上调 FUT3 的表达（图 3）。FUT3 表达的增加会加速 I 型 TGF $\beta$$\beta$beta\beta 受体（TGF $\beta$$\beta$beta\beta RI）的岩藻糖基化，从而激活 TGF- $\beta$$\beta$beta\beta 信号通路 [74]。除了在 miRNA 处理中的作用外，KSRP 还可能调节包括 CD44 和 FGFR2 在内的一系列前体 mRNA 的 AS 事件，以破坏 TGF- $\beta$$\beta$beta\beta 诱导的 EMT [107]。最近的证据表明，多嘧啶束结合蛋白 3（PTBP3）通过多种转录后作用，如 AS、mRNA 稳定性和翻译激活，在各种癌症类型中发挥着转移促进因子的作用 [75，146-148]。据报道，PTBP3 通过与 CAV1 内含子富含 CU 的区域结合，降低 CAV1 $\alpha$$\alpha$alpha\alpha 异构体的表达，从而发挥其 AS 作用，抑制胃癌细胞在体外的迁移和侵袭，以及体内的淋巴结转移 [75]。

Interestingly, PTBP3 influences the AS of ncRNAs. Yang et al. demonstrated that PTBP3 promotes HCC cell metastasis by downregulating miR-612, a splicing variant of lncRNA-NEAT1 [146].
有趣的是，PTBP3 会影响 ncRNA 的 AS。Yang等人证实，PTBP3通过下调lncRNA-NEAT1的剪接变体miR-612来促进HCC细胞转移[146]。

APA, the same as AS, is a post-transcriptioalant regulatory mechanism that regulates gene expression by RNA $3^{\prime }$$3^{\prime }$3^(')3^{\prime} processing machinery, resulting in distinct mRNA isoforms that differ at either the coding sequence (CDS) or $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR [149-152]. RBP-mediated APA of target mRNAs is mainly accomplished by controlling the cleavage and polyadenylation of 3 ’ terminus [150,153]. Therefore, APA regulates the function of proteins by modifying the CDS of target mRNAs and affects the stability, translational efficiency, and subcellular localization of target mRNAs by altering the length of their $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR. Clinically, aberrant APA on the $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR of precursor mRNA modulated by RBPs often occurs in cancer metastasis [31, 154-158].
APA与AS一样，是一种转录后调控机制，通过RNA $3^{\prime }$$3^{\prime }$3^(')3^{\prime} 加工机制调控基因表达，从而产生在编码序列（CDS）或 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR上不同的mRNA异构体[149-152]。RBP 介导的目标 mRNA 的 APA 主要是通过控制 3' 末端的裂解和多腺苷酸化来实现的 [150,153]。因此，APA 通过修饰靶 mRNA 的 CDS 来调节蛋白质的功能，并通过改变其 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR 的长度来影响靶 mRNA 的稳定性、翻译效率和亚细胞定位。临床上，受 RBPs 调节的前体 mRNA $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR 上的异常 APA 常发生在癌症转移中 [31, 154-158]。

CPEB proteins are critical factors controlling the elongation of poly (A) tail during translation. TWIST1 is an important transcriptional factor contributing to EMT and tumor metastasis [159]. TWIST1 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR contains two cytoplasmic polyadenylation elements (CPEs). CPEB1 and CPEB2 negatively regulate the translation of TWIST1, a known mesenchymal transcriptional regulator in EMT and metastasis, through binding to the CPEs in the $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR of TWIST1 transcripts [155]. Moreover, CPEB1 deficiency increases polyadenylation of MMP9 mRNA and enhances MMP9 protein expression, accelerating EMT and breast cancer metastasis [41]. CPEB3, like CPEB1/2, has recently been shown to inhibit HCC metastasis through translational suppression of MTDH mRNA in a CPE-dependent manner [38]. Furthermore, CPEB3 can bind to the $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR of the JAK1 mRNA and constrain the proliferation and invasion of colorectal cancer cells [34]. Nudix hydrolase 21 (NUDT21), another crucial APA modulator, exerts tumor-suppressive effects on
CPEB 蛋白是控制翻译过程中聚（A）尾伸长的关键因子。TWIST1 是一种重要的转录因子，有助于 EMT 和肿瘤转移 [159]。TWIST1 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR 包含两个细胞质多腺苷酸化元件（CPE）。CPEB1 和 CPEB2 通过与 TWIST1 转录本 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR 中的 CPEs 结合，负向调节 TWIST1 的翻译，TWIST1 是已知的间充质转录调节因子，参与 EMT 和转移 [155]。此外，CPEB1 缺乏会增加 MMP9 mRNA 的多腺苷酸化，并增强 MMP9 蛋白表达，加速 EMT 和乳腺癌转移 [41]。CPEB3 与 CPEB1/2 一样，最近被证明可通过 CPE 依赖性方式抑制 MTDH mRNA 的翻译，从而抑制 HCC 转移 [38]。此外，CPEB3 还能与 JAK1 mRNA 的 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR 结合，限制结直肠癌细胞的增殖和侵袭 [34]。Nudix hydrolase 21（NUDT21）是另一个重要的 APA 调节因子，它对以下细胞具有抑制肿瘤的作用
human cancers. In bladder cancer, the reduced expression of NUDT21 is associated with a poor prognosis. NUDT21 significantly inhibits the cell proliferation, migration, and invasion of bladder cancer cells through controlling the $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR length of LIMK2 and ANXA2 [31].
人类癌症。在膀胱癌中，NUDT21 的表达减少与预后不良有关。NUDT21 通过控制 LIMK2 和 ANXA2 的 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR 长度，可明显抑制膀胱癌细胞的增殖、迁移和侵袭 [31]。

RNA stability primarily depends on mRNA nucleotide sequence and modifications and is determined by its $5^{\prime }{\mathrm{m}}^7\mathrm{G}$$5^{\prime }{\mathrm{m}}^7\mathrm{G}$5^(')m^(7)G5^{\prime} \mathrm{m}^{7} \mathrm{G} cap and $3^{\prime }$$3^{\prime }$3^(')3^{\prime} poly (A) tail to regulate mRNA decay [160]. Specifically, mRNA degradation is modulated by two main mechanisms, one of which initiates with the deadenylation of the $3^{\prime }$$3^{\prime }$3^(')3^{\prime} poly (A) tail, followed by $5^{\prime }$$5^{\prime }$5^(')5^{\prime} decapping and $5^{\prime }$$5^{\prime }$5^(')5^{\prime} to $3^{\prime }$$3^{\prime }$3^(')3^{\prime} direction degradation; and the other starts after the hydrolysis of the $3^{\prime }$$3^{\prime }$3^(')3^{\prime} poly (A) tail, and then degrades from $3^{\prime }$$3^{\prime }$3^(')3^{\prime} to $5^{\prime }$$5^{\prime }$5^(')5^{\prime} [161]. So far, the most classical sequence of $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR involved in destabilization of mRNA is the AU-rich element (ARE), which is estimated to exist in $16\mathrm{\%}$$16\mathrm{\%}$16%16 \% of all human transcripts $[162,163]$$[162,163]$[162,163][162,163]. Accumulating evidence has revealed that multiple RBPs, such as ARE RNA binding protein 1 (AUF1) [33], CUGBP Elav-like family member 2 (CELF2) [164], HuR [165], Insulin-like growth factor 2 mRNA protein (IGF2BP) family [166], QKI-5 [30], RBMS3 [167], and TARBP2 [80], play an important role in cancer progression and metastasis by stabilizing or destabilizing specific target mRNAs.
RNA 的稳定性主要取决于 mRNA 的核苷酸序列和修饰，并由其 $5^{\prime }{\mathrm{m}}^7\mathrm{G}$$5^{\prime }{\mathrm{m}}^7\mathrm{G}$5^(')m^(7)G5^{\prime} \mathrm{m}^{7} \mathrm{G} 帽和 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} 多聚（A）尾决定，从而调节 mRNA 的衰变 [160]。具体来说，mRNA 的降解主要受两种机制的调控，其中一种机制以 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} 多聚（A）尾的去烯化为起点，然后是 $5^{\prime }$$5^{\prime }$5^(')5^{\prime} 去帽和 $5^{\prime }$$5^{\prime }$5^(')5^{\prime} 至 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} 方向的降解；另一种机制则是在 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} 多聚（A）尾水解后开始，然后从 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} 至 $5^{\prime }$$5^{\prime }$5^(')5^{\prime} 方向降解 [161]。迄今为止，参与破坏 mRNA 稳定的 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR 中最经典的序列是富含 AU 的元素（ARE），据估计，在所有人类转录本 $[162,163]$$[162,163]$[162,163][162,163] 中， $16\mathrm{\%}$$16\mathrm{\%}$16%16 \% 中都存在这种元素。越来越多的证据表明，多种 RBPs，如 ARE RNA 结合蛋白 1（AUF1）[33]、CUGBP Elav-like 家族成员 2（CELF2）[164]、HuR[165]、胰岛素样生长因子 2 mRNA 蛋白（IGF2BP）家族[166]、QKI-5[30]、RBMS3 [167] 和 TARBP2 [80]，通过稳定或破坏特定靶 mRNA 的稳定，在癌症进展和转移中发挥着重要作用。

Goodarzi et al. identified a group of RNA cis-elements (sRSE) responsible for RNA stability. Transcripts containing the sRSE exhibit reduced mRNA stability in highly metastatic breast cancer cells. They then computationally identified and biochemically validated TARBP2, an SRSE-binding factor that is overexpressed in metastatic cancer cells. By interacting with their sRSE elements, TARBP2 destabilizes APP and ZNF395 mRNA and promotes breast cancer cell invasion and colonization [80]. AUF1, also known as hnRNP D, interacts with the AREs of target mRNA and predominantly triggers mRNA degradation in an
Goodarzi 等人发现了一组负责 RNA 稳定性的 RNA 顺式元件（sRSE）。在高度转移性乳腺癌细胞中，含有 sRSE 的转录本会降低 mRNA 的稳定性。随后，他们通过计算确定并生化验证了 TARBP2，这是一种在转移性癌细胞中过度表达的 SRSE 结合因子。通过与它们的 sRSE 元素相互作用，TARBP2 破坏了 APP 和 ZNF395 mRNA 的稳定性，促进了乳腺癌细胞的侵袭和定植[80]。AUF1 又称 hnRNP D，它与目标 mRNA 的 AREs 相互作用，并主要触发 mRNA 降解。

Fig. 3. The abnormal expression and interaction of RBPs influences cancer metastasis by regulating various alternative splicing events. BioRender (https://biorender com) was used to create the image.
图 3.RBPs 的异常表达和相互作用通过调节各种替代剪接事件影响癌症转移。使用 BioRender ( https://biorender com) 绘制图像。

ARE-dependent manner [168]. It has been shown that high levels of AUF1 are associated with metastasis and that AUF1 depletion leads to reduced ERK1/2 and AKT phosphorylation in colorectal cancer [169]. Mechanistically, AUF1 facilitated mesenchymal properties and promoted stemness by direct RNA-binding and stabilization of PDK (an AKT activator) and EMT transcriptional factors (SNAI1 and TWIST1) mRNAs [33,170]. Moreover, there is increasing evidence showing that HuR directly interacts with and stabilizes a variety of mRNAs and ncRNAs involved in cancer metastasis, such as FOXQ1, MMP1, SNAI1, EGFR, IL-8, PTBP1, TXNIP, lncRNA-HGBC, lncRNA-HOTAIR, etc. [49, 52, 116, $124,165,171-174]$$124,165,171-174]$124,165,171-174]124,165,171-174]. Importantly, HuR interaction with some transcripts is revealed to be stabilized by distinct circRNAs [173,174], illustrating the complexity of HuR interaction with ncRNAs. The role of the IGF2BP family in cancer progression and metastasis is recognized in an increasing body of literature, the majority of which has been thoroughly reviewed [166, 175-177]. According to recent research, IGF2BP2 and IGF2BP3 collaborate to promote breast cancer metastasis by degrading progesterone receptor (PR) mRNA [178]. Interestingly, in melanoma, p62/SQSTM1 cooperates with IGF2BP1 to stabilize the mRNA of several metastatic factors, including FERMT2, suggesting that certain proteins may play specialized roles in cancer progression via interactions with IGF2BPs [179]. RBPs that regulate EMT-related factors play a key role in cancer metastasis regulation. Recently, RBMS3 was identified as a novel EMT effector that improves the stability of the EMT-associated transcription factor PRRX1, hence contributing to spontaneous metastasis in a mouse model of breast cancer [167]. In addition, PTBP3 prevents the mRNA degradation of ZEB1, a well-known EMT transcription factor, inducing EMT and promoting metastasis of breast cancer cells [147]. Furthermore, our recent research demonstrated that QKI-5 inhibited TGF- $\beta$$\beta$beta\beta-induced EMT and metastasis by directly interacting with TGF $\beta$$\beta$beta\beta R1 mRNA $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR in LUAD, resulting in TGF $\beta$$\beta$beta\beta R1 mRNA degradation [30].
ARE依赖的方式 [168]。研究表明，高水平的AUF1与转移有关，而AUF1耗竭会导致结直肠癌中ERK1/2和AKT磷酸化减少[169]。从机制上讲，AUF1通过直接RNA结合和稳定PDK（一种AKT激活因子）和EMT转录因子（SNAI1和TWIST1）mRNA，促进间充质特性和干性[33,170]。此外，越来越多的证据表明，HuR 直接与多种涉及癌症转移的 mRNA 和 ncRNA 相互作用并使其稳定，如 FOXQ1、MMP1、SNAI1、表皮生长因子受体、IL-8、PTBP1、TXNIP、lncRNA-HGBC、lncRNA-HOTAIR 等。[49, 52, 116, $124,165,171-174]$$124,165,171-174]$124,165,171-174]124,165,171-174] 。重要的是，HuR 与一些转录本的相互作用被发现是由不同的 circRNAs 稳定的 [173,174]，这说明了 HuR 与 ncRNAs 相互作用的复杂性。越来越多的文献认识到了 IGF2BP 家族在癌症进展和转移中的作用，其中大部分文献已被详细综述[166, 175-177]。根据最近的研究，IGF2BP2 和 IGF2BP3 通过降解孕酮受体（PR）mRNA 共同促进乳腺癌的转移[178]。有趣的是，在黑色素瘤中，p62/SQSTM1 与 IGF2BP1 合作稳定包括 FERMT2 在内的几种转移因子的 mRNA，这表明某些蛋白质可能通过与 IGF2BPs 的相互作用在癌症进展中发挥特殊作用 [179]。调控 EMT 相关因子的 RBPs 在癌症转移调控中发挥着关键作用。最近，RBMS3 被鉴定为一种新型的 EMT 效应因子，可提高 EMT 相关转录因子 PRRX1 的稳定性，从而促进乳腺癌小鼠模型的自发转移 [167]。 此外，PTBP3 还能阻止著名的 EMT 转录因子 ZEB1 的 mRNA 降解，从而诱导 EMT 并促进乳腺癌细胞的转移 [147]。此外，我们最近的研究表明，QKI-5 通过与 LUAD 中 TGF $\beta$$\beta$beta\beta R1 mRNA $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR 直接相互作用，导致 TGF $\beta$$\beta$beta\beta R1 mRNA 降解，从而抑制了 TGF- $\beta$$\beta$beta\beta 诱导的 EMT 和转移 [30]。

RBP-mediated intracellular localization regulates the stability and translation of target mRNAs preliminarily by interacting with the specific sequences within their 3’ UTR, which is critical for multiple cellular processes, including cancer biology [180-182]. The subcellular localization of mRNAs regulated by RBPs involves several steps and requires the coordinated participation of a variety of protein factors. In this regulation process, the cis motif and zipcode element in mRNA $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR are very important for the recognition between RBP and mRNAs [183]. Currently, multiple RBPs such as CPEB1, La ribonucleoprotein domain family member 6 (LARP6), T-cell restriction intracellular antigen 1 (TIA1), and Z-nucleic acid binding protein 1 (ZBP1) are implicated in RNA localization and regulation of EMT and cancer metastasis [41, 184-187].
RBP 介导的胞内定位通过与目标 mRNA 的 3' UTR 内的特定序列相互作用，初步调控目标 mRNA 的稳定性和翻译，这对包括癌症生物学在内的多种细胞过程至关重要 [180-182]。受 RBPs 调节的 mRNA 亚细胞定位涉及多个步骤，需要多种蛋白因子的协调参与。在这一调控过程中，mRNA $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR 中的顺式图案和 zipcode 元素对于 RBP 与 mRNA 之间的识别非常重要 [183]。目前，CPEB1、La 核糖核蛋白结构域家族成员 6（LARP6）、T 细胞限制性细胞内抗原 1（TIA1）和 Z 核酸结合蛋白 1（ZBP1）等多种 RBPs 与 RNA 定位及 EMT 和癌症转移的调控有关 [41，184-187]。

CPEB-mediated ZO-1 mRNA localization has been elucidated to be responsible for epithelial tight-junction assembly and cell polarity [188]. In addition, CPEB1 mediates EMT and breast cancer metastasis partially by regulating MMP9 mRNA expression [41]. LARP6 serves as a key player in controlling RNA localization. In breast cancer, LARP6-mediated intracellular localization of ribosomal protein-coding mRNAs (RP-mRNAs) contributes to their translation during cell migration and EMT [187]. Chemotaxis and motility are specialized traits that direct cell migration and cancer metastasis. A study in the social amoeba Dictyostelium discoideum demonstrated that the Pumilio-related RNA-binding protein Puf118 is required for the polarized localization of Puf118-targeting mRNAs during dynamic cell migration [186]. TIA1 is the main component of stress granules (SGS) and participates in multiple biological processes, including cell stress, cancer metastasis, and immune escape. TIA1 interacts with p53 mRNAs and controls its localization and expression during B lymphocyte activation [189]. Moreover, TIA1 binds to VEGF mRNAs and regulates VEGF isoform expression, involving it in angiogenesis, metastasis, and bevacizumab resistance [185]. ZBP1 was identified as a crucial regulator of the subcellular
CPEB 介导的 ZO-1 mRNA 定位已被证实负责上皮细胞紧密连接组装和细胞极性 [188]。此外，CPEB1 部分通过调节 MMP9 mRNA 的表达来介导 EMT 和乳腺癌转移 [41]。LARP6 是控制 RNA 定位的关键角色。在乳腺癌中，LARP6 介导的核糖体蛋白编码 mRNA（RP-mRNA）胞内定位有助于它们在细胞迁移和 EMT 过程中的翻译 [187]。趋化性和运动性是指导细胞迁移和癌症转移的特化特征。在盘基变形虫中进行的一项研究表明，在动态细胞迁移过程中，Pumilio 相关 RNA 结合蛋白 Puf118 是 Puf118 靶向 mRNA 极化定位所必需的 [186]。TIA1 是应激颗粒（SGS）的主要成分，参与多种生物过程，包括细胞应激、癌症转移和免疫逃逸。TIA1 与 p53 mRNA 相互作用，并在 B 淋巴细胞活化过程中控制其定位和表达 [189]。此外，TIA1 还能与血管内皮生长因子 mRNA 结合并调节血管内皮生长因子异构体的表达，使其参与血管生成、转移和贝伐珠单抗抗性[185]。ZBP1 被确定为亚细胞内血管内皮生长因子表达的关键调控因子[185]。
localization of mRNAs. In breast cancer, ZBP1 is decreased and associated with cancer metastasis. Mechanistically, ZBP1 binds to target mRNAs, including E-cadherin, $\alpha$$\alpha$alpha\alpha-actinin, $\beta$$\beta$beta\beta-actin, and the Arp $2/3$$2/3$2//32 / 3 complex, and facilitates their localization to regulate cancer metastasis [184].
mRNA 的定位。在乳腺癌中，ZBP1 的减少与癌症转移有关。从机理上讲，ZBP1 可与目标 mRNA 结合，包括 E-cadherin、 $\alpha$$\alpha$alpha\alpha -actinin、 $\beta$$\beta$beta\beta -actin 和 Arp $2/3$$2/3$2//32 / 3 复合物，并促进其定位以调控癌症转移 [184]。

The translation process can be finely divided into three coordinated steps: initiation, elongation, and termination. Generally, most mRNAs’ translational regulation occurs at the initial stage, when RBPs can interact with the 5 ’ or 3 ’ UTR of target mRNAs via different binding affinities, resulting in different translation efficiencies [190]. Several studies have highlighted the biological roles of RBPs in translational control during EMT and metastasis of human cancers [38, 76, 191-195].
翻译过程可细分为三个协调步骤：启动、延伸和终止。一般来说，大多数 mRNA 的翻译调控发生在初始阶段，此时 RBPs 可通过不同的结合亲和力与目标 mRNA 的 5' 或 3' UTR 相互作用，从而导致不同的翻译效率 [190]。一些研究强调了 RBPs 在人类癌症 EMT 和转移过程中翻译控制的生物学作用 [38、76、191-195]。

The eukaryotic translation initiation factor (eIF) 4F complex is required for translation initiation by recruiting ribosomes to mRNA and mediating initiation complex assembly [196]. eIF4E, as a subunit of eIF4F, is in charge of mRNA 5’-cap-binding. Although eIF4E-mediated cap-dependent translation is universal for all mRNAs, emerging evidence suggests that changes in eIF4E levels are more likely to influence the translation of cancer-related mRNAs [196]. Importantly, eIF4E overexpression and phosphorylation are associated with metastasis in a variety of cancers [197-200]. Phosphorylation of eIF4E (eIF4E S209A) has been shown to be essential for lung metastasis in vivo by promoting the translation of SNAI1 and MMP3 mRNAs [201]. Moreover, eIF4E S209A deficient mice with postpartum breast cancer (PPBC) exhibited anti-lung metastasis capabilities compared to wild-type mice, mechanistically through inhibition of IL33 translation [202]. MSI proteins, including MSI1 and MSI2, have been extensively investigated for their critical roles in regulating diverse biological processes, including cancer [203]. MSI appears to regulate protein translation by binding to the $3^{\prime }$$3^{\prime }$3^(')3^{\prime} end-consensus elements of target mRNAs. Two RRMs located at the N-terminal of each MSI protein mediate MSI interaction with target mRNAs [204,205]. Several recent studies reveal that MSI plays an important role in cancer progression and metastasis. MSI1 has been shown to suppress Timp3 mRNA translation by binding to its $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR, thus promoting MMP9-mediated breast metastasis [54]. MSI2 has been shown to enhance direct translational targets relevant to EMT, including TGFßRI, SMAD3, and SNAI1, indicating pro-metastatic potential [61]. According to a recent study, MSI2 promotes pancreatic cancer cell invasion by directly interacting with SAV1 and MOB1 mRNA to limit their protein levels [63]. hnRNP E1, an RBP from the hnRNP family, has been demonstrated to increase the invasiveness of EMT cells by promoting inhibin $\beta$$\beta$beta\beta A translation activity [192]. Another conserved RBP, CSDE1, also known as UNR, is predominantly located in the cytoplasm and regulates the stability and translation of target mRNAs [79]. Wurth and colleagues reveal that CSDE1 drives the translation of Vimentin and RAC1 mRNAs, and promotes the invasion and metastasis of melanoma [76]. Importantly, methyladenosine $\left({\mathrm{m}}^6\mathrm{A}\right)$$\left({\mathrm{m}}^6\mathrm{A}\right)$(m^(6)(A))\left(\mathrm{m}^{6} \mathrm{~A}\right) is one of the most conserved and abundant RNA modification forms of eukaryotic mRNA, and is a critical post-transcriptional mechanism for regulating translation [206]. We will discuss it more in detail in the subsequent part
真核生物翻译起始因子（eIF）4F 复合物是翻译起始所必需的，它将核糖体募集到 mRNA 上并介导起始复合物的组装[196]。虽然 eIF4E 介导的帽子依赖性翻译对所有 mRNA 都适用，但新出现的证据表明，eIF4E 水平的变化更有可能影响癌症相关 mRNA 的翻译 [196]。重要的是，eIF4E 的过表达和磷酸化与多种癌症的转移有关 [197-200]。研究表明，eIF4E 的磷酸化（eIF4E S209A）通过促进 SNAI1 和 MMP3 mRNA 的翻译，对体内肺转移至关重要 [201]。此外，与野生型小鼠相比，eIF4E S209A 缺失的产后乳腺癌（PPBC）小鼠表现出抗肺转移能力，其机制是通过抑制 IL33 的翻译[202]。包括 MSI1 和 MSI2 在内的 MSI 蛋白因其在调控包括癌症在内的各种生物过程中的关键作用而受到广泛研究 [203]。MSI 似乎通过与目标 mRNA 的 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} 端部共识元件结合来调节蛋白质翻译。位于每个 MSI 蛋白 N 端的两个 RRM 介导了 MSI 与目标 mRNA 的相互作用 [204,205]。最近的一些研究表明，MSI 在癌症进展和转移中发挥着重要作用。研究表明，MSI1 通过与 Timp3 mRNA 的 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR 结合，抑制了 Timp3 mRNA 的翻译，从而促进了 MMP9 介导的乳腺癌转移 [54]。研究表明，MSI2 可增强与 EMT 相关的直接翻译靶标，包括 TGFßRI、SMAD3 和 SNAI1，表明其具有促进转移的潜力[61]。 最近的一项研究表明，MSI2通过直接与SAV1和MOB1 mRNA相互作用来限制它们的蛋白水平，从而促进胰腺癌细胞的侵袭[63]。hnRNP E1是hnRNP家族的一种RBP，已被证实可通过促进抑制素 $\beta$$\beta$beta\beta A的翻译活性来增加EMT细胞的侵袭性[192]。另一种保守的 RBP--CSDE1（又称 UNR）主要位于细胞质中，调节靶 mRNA 的稳定性和翻译 [79]。Wurth 及其同事发现，CSDE1 可驱动 Vimentin 和 RAC1 mRNA 的翻译，并促进黑色素瘤的侵袭和转移 [76]。重要的是，甲基腺苷 $\left({\mathrm{m}}^6\mathrm{A}\right)$$\left({\mathrm{m}}^6\mathrm{A}\right)$(m^(6)(A))\left(\mathrm{m}^{6} \mathrm{~A}\right) 是真核生物 mRNA 中最保守、最丰富的 RNA 修饰形式之一，也是调控翻译的关键转录后机制 [206]。我们将在下一部分中详细讨论它

The functions and underlying mechanisms of RNA methylation in biological processes have become an emerging investigation focus. The most prevalent modification of eukaryotic mRNAs is the ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} modification, which leads to the regulation of mRNA stability, splicing, and translation [207,208]. The players regulating ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} are divided into three categories based on their distinct functions: “writers” of methyltransferases (e.g., methyltransferase-like (METTL) 3/14, WTAP, and KIAA1429), “erasers” of demethylases (e.g., FTO and ALKBH5), and “readers” of effectors (e.g., YTHDF1/2/3 and YTHDC1/2) [209-212]. Here, we will provide an overview of the functions and mechanisms of
RNA 甲基化在生物过程中的功能和内在机制已成为新的研究重点。真核生物 mRNA 最常见的修饰是 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 修饰，它导致 mRNA 稳定性、剪接和翻译的调控 [207,208]。调节 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 的角色根据其不同的功能可分为三类：甲基转移酶的 "写入者"（如甲基转移酶样（METTL）3/14、WTAP 和 KIAA1429）、去甲基化酶的 "擦除者"（如 FTO 和 ALKBH5）以及效应物的 "读取者"（如 YTHDF1/2/3 和 YTHDC1/2） [209-212]。在此，我们将概述这些作用的功能和机制。
these regulators of mRNA $-{\mathrm{m}}^6\mathrm{A}$$-{\mathrm{m}}^6\mathrm{A}$-m^(6)A-\mathrm{m}^{6} \mathrm{~A} modification associated with tumor metastasis (Fig. 4).
这些与肿瘤转移相关的 mRNA $-{\mathrm{m}}^6\mathrm{A}$$-{\mathrm{m}}^6\mathrm{A}$-m^(6)A-\mathrm{m}^{6} \mathrm{~A} 修饰调节因子（图 4）。

Panneerdoss et al. found the same inhibition effect on breast cancer cell growth and invasion after silencing either METTL14 or ALKBH5 to change the corresponding ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} levels. In detail, METTL14 and ALKBH5 promote the expression of each other, and inhibit the expression of YTHDF3, a reader of ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A}. Moreover, METTL14 and ALKBH5 upregulate HuR, which in turn promotes the stability of METTL14 and ALKBH5 and target mRNAs to form a positive feedback loop (Fig. 4A). They revealed a novel mechanism for ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} writers and erasers in cancer, and presented a network regulation among writers-erasers-readers to ensure target gene stability during promoting breast cancer growth and metastasis [213]. METTL3 forms an ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} methyltransferase complex with METTL14 and WTAP to enhance HuR-dependent ZMYM1 mRNA stability, facilitating EMT and gastric cancer metastasis [212] (Fig. 4B). KIAA1429, another “writer” of ${\mathrm{m}}^6$${\mathrm{m}}^6$m^(6)\mathrm{m}^{6} A methylation, exhibits oncogenic and pro-metastatic effects in liver cancer. Mechanistically, KIAA1429 promotes the ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} methylation on the $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR of GATA3 mRNA, which hinders HuR from binding to and stabilizing GATA3 mRNA [214] (Fig. 4B). High METTL3 expression is associated with a bad outcome in HCC patients. METTL3 Knockdown inhibits HCC cell proliferation and invasion in a YTHDF2-dependent manner by abolishing SOCS2 mRNA $m^6\mathrm{A}$$m^6\mathrm{A}$m^(6)Am^{6} \mathrm{~A} [215] (Fig. 4C). However, METTL14 functions as a suppressor during colorectal cancer metastasis. It inhibits colorectal cancer cell
Panneerdoss等人发现，沉默METTL14或ALKBH5以改变相应的 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 水平，对乳腺癌细胞的生长和侵袭也有同样的抑制作用。具体来说，METTL14 和 ALKBH5 相互促进对方的表达，并抑制 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 的阅读器 YTHDF3 的表达。此外，METTL14和ALKBH5上调HuR，HuR又促进METTL14和ALKBH5以及靶mRNA的稳定，形成正反馈环（图4A）。他们揭示了癌症中 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 书写者和擦除者的新机制，并提出了书写者-擦除者-阅读者之间的网络调控，以确保靶基因在促进乳腺癌生长和转移过程中的稳定性[213]。METTL3与METTL14和WTAP形成 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 甲基转移酶复合物，增强HuR依赖的ZMYM1 mRNA稳定性，促进EMT和胃癌转移[212]（图4B）。KIAA1429 是 ${\mathrm{m}}^6$${\mathrm{m}}^6$m^(6)\mathrm{m}^{6} A 甲基化的另一位 "作家"，在肝癌中表现出致癌和促进转移的作用。从机理上讲，KIAA1429会促进GATA3 mRNA的 $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR上的 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 甲基化，从而阻碍HuR与GATA3 mRNA结合并使其稳定[214]（图4B）。METTL3 的高表达与 HCC 患者的不良预后有关。METTL3 敲除可通过废除 SOCS2 mRNA $m^6\mathrm{A}$$m^6\mathrm{A}$m^(6)Am^{6} \mathrm{~A} [215]，以 YTHDF2 依赖性方式抑制 HCC 细胞的增殖和侵袭（图 4C）。然而，METTL14 在结直肠癌转移过程中起抑制作用。它抑制结直肠癌细胞
invasion and metastasis via ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} modification-mediated SOX4 degradation, which is YTHDF2-dependent [216] (Fig. 4D). Evidence suggests that the “readers” may have separate functions in regulating ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} modified mRNAs. Sublethal heat stress dramatically increases YTHDF1, which then enhances HCC metastasis by binding to EGFR mRNAs and increasing translation [195]. YTHDF2 has been involved in the progression of cancer via regulating target mRNA stability and decay [217, 218]. YTHDF2-depletion boosts tumor cell translation and protein synthesis rates, inhibiting tumor cell growth and encouraging the EMT process in MYC-driven breast cancer [72]. Jin et al. have explored the involvement of ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} readers in regulating METTL3 and ALKBH5-mediated NSCLC progression [219,220]. They found that METTL3 increased the ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} modification of YAP mRNA, which resulted in cytoplasmic YTHDF1/3 cooperating with eIF3b to promote YAP mRNA translation, triggering drug resistance and NSCLC metastasis [219]. In addition, ALKBH5 has been found to inhibit NSCLC growth and metastasis through reducing ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} modification of YAP and inhibiting YTHDF3-dependent YAP expression. Importantly, they revealed competing machinery for YTHDF1 and YTHDF2 binding to YTHDF3, and the YTHDF1/3 and YTHDF2/3 complexes that recognize ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} on YAP mRNA had opposing effects on YAP mRNA destiny. YTHDF1/3 stimulates translation of YAP mRNA by interacting with eIF3a, whereas YTHDF2/3 promotes YAP mRNA degradation via the AGO2 system. Moreover, low expression of ALKBH5 and YTHDF2, as well as high
通过 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 修饰介导的SOX4降解，这种降解依赖于YTHDF2[216]（图4D）。有证据表明，"读者 "在调节 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 修饰的mRNA方面可能具有不同的功能。亚致死性热应激会显著增加 YTHDF1，然后它通过与表皮生长因子受体 mRNA 结合并增加翻译来促进 HCC 转移 [195]。YTHDF2 通过调节靶 mRNA 的稳定性和衰变参与癌症的进展 [217, 218]。在 MYC 驱动的乳腺癌中，YTHDF2 的缺失可提高肿瘤细胞的翻译和蛋白质合成率，抑制肿瘤细胞生长并促进 EMT 过程 [72]。Jin 等人探讨了 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 阅读器参与调控 METTL3 和 ALKBH5 介导的 NSCLC 进展 [219,220]。他们发现，METTL3 增加了 YAP mRNA 的 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 修饰，导致胞质 YTHDF1/3 与 eIF3b 合作促进 YAP mRNA 翻译，引发耐药性和 NSCLC 转移 [219]。此外，研究还发现ALKBH5可通过减少YAP的 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 修饰和抑制YTHDF3依赖的YAP表达来抑制NSCLC的生长和转移。重要的是，他们揭示了YTHDF1和YTHDF2与YTHDF3结合的竞争机制，识别YAP mRNA上 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 的YTHDF1/3和YTHDF2/3复合物对YAP mRNA命运的影响是相反的。YTHDF1/3通过与eIF3a相互作用刺激YAP mRNA的翻译，而YTHDF2/3则通过AGO2系统促进YAP mRNA的降解。此外，低表达 ALKBH5 和 YTHDF2 以及高表达 ALKBH5 和 YTHDF2

Fig. 4. Critical roles of ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} regulators and effectors in cancer metastasis. (A) Cross-talk between the writer (METTL14), eraser (ALKBH5), and readers (HuR, YTHDF2/3, etc.) to regulate the stability and degradation of target mRNAs associated with EMT and metastasis. (B) HuR is essential for the writers METTL3 and KIAA1429 to regulate the ${\mathrm{m}}^6$${\mathrm{m}}^6$m^(6)\mathrm{m}^{6} A modification of target mRNAs. (C and D) YTHDF2 promotes the degradation of target mRNAs, which may have opposing effects on cancer metastasis in different types of cancer. (E) YTHDF1 and YTHDF2 competitively bind to YTHDF3 to form the YTHDF1/3 and YTHDF2/3 complexes, which recognize ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} on YAP mRNA and have opposite effects on the fate of YAP mRNA. BioRender (https://biorender.com) was used to create the image.
图 4. ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 调控因子和效应因子在癌症转移中的关键作用。(A) 写者（METTL14）、擦除者（ALKBH5）和阅读者（HuR、YTHDF2/3 等）之间的交叉对话，以调节与 EMT 和转移相关的靶 mRNA 的稳定性和降解。(B）HuR是METTL3和KIAA1429调控靶mRNA的 ${\mathrm{m}}^6$${\mathrm{m}}^6$m^(6)\mathrm{m}^{6} A修饰的必要写入因子。(C和D）YTHDF2促进靶mRNA的降解，这可能对不同类型癌症的癌症转移产生相反的影响。(E）YTHDF1 和 YTHDF2 竞争性地与 YTHDF3 结合形成 YTHDF1/3 和 YTHDF2/3 复合物，它们识别 YAP mRNA 上的 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 并对 YAP mRNA 的命运产生相反的影响。使用 BioRender ( https://biorender.com) 绘制图像。
expression of YTHDF1, were found in NSCLC samples, tipping the balance in favor of YAP overexpression, which promotes tumor growth and metastasis [220] (Fig. 4E). Taken together, these findings show that ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} methylation-mediated mRNA modification is vital for cancer metastasis via interacting with RBPs.
在 NSCLC 样本中发现了 YTHDF1 的表达，使 YAP 过表达的天平倾向于促进肿瘤生长和转移的 YAP [220]（图 4E）。综上所述，这些研究结果表明， ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 甲基化介导的 mRNA 修饰通过与 RBPs 相互作用对癌症转移至关重要。

Herein, we have focused on reviewing the main mechanistic role of RBPs in cancer metastasis. In fact, emerging evidence endows RBPs with new functions, such as chromatin remodeling and DNA damage repair [221-223]. Although one RBP can generally regulate multiple target mRNAs at the post-transcriptional level, in other cases, RBP-RBP or RBP-ncRNA combinations may regulate a specific target mRNA, which yields different outcomes depending on synergistic and/or antagonistic interactions [25].
在此，我们重点回顾了 RBPs 在癌症转移中的主要机制作用。事实上，新出现的证据赋予了 RBPs 新的功能，如染色质重塑和 DNA 损伤修复 [221-223]。虽然一种 RBP 通常可以在转录后水平调控多个靶 mRNA，但在其他情况下，RBP-RBP 或 RBP-ncRNA 组合可能会调控特定的靶 mRNA，从而根据协同和/或拮抗相互作用产生不同的结果[25]。

As well-described above, RBP-mediated post-transcriptional regulation of RNA biology is involved in EMT, invasion and cancer metastasis (Table 1), suggesting that RBP-based therapy is a promising strategy to intervene in cancer metastasis. Therefore, the development of RBPbased targeted drugs has garnered more attention in the past decades. With the deepening of RBP research and the continuous development of drug screening and deep-running technologies, some RBP-targeting approaches are undergoing pre-clinical and clinical trials to evaluate their application potential. In this section, we will review several candidate therapeutics, including small molecule drugs, antisense oligonucleotides (ASOs), and proteolysis-targeting chimeras (PROTACs), that target the metastasis-related RBPs and have the potential to intervene in cancer metastasis.
如上所述，RBP 介导的转录后 RNA 生物学调控参与了 EMT、侵袭和癌症转移（表 1），这表明基于 RBP 的治疗是干预癌症转移的一种有前景的策略。因此，基于 RBP 的靶向药物的开发在过去几十年中受到了越来越多的关注。随着 RBP 研究的深入以及药物筛选和深度运行技术的不断发展，一些 RBP 靶向方法正在进行临床前和临床试验，以评估其应用潜力。本节将综述几种候选疗法，包括小分子药物、反义寡核苷酸（ASOs）和蛋白水解靶向嵌合体（PROTACs），它们都以转移相关的RBPs为靶点，具有干预癌症转移的潜力。

Small molecule inhibitors are by far the most common RBP-targeting tactics to limit RBP function during cancer progression. However, despite the fact that a large number of RBPs are involved in cancer and metastasis, only a limited number of small molecules with therapeutic potential have been developed for a handful of RBPs. This could be because the majority of RBPs are considered “undruggable” due to the lack of traditional pockets or functional epitopes that are frequently found in classical enzymes and membrane proteins [224]. Besides that, compound-screening methods continue to have some limitations and difficulties [225]. In any case, numerous small molecules have been screened for RBPs with well-defined roles in cancer and metastasis, such as HuR , eIF4E, LIN28, MSI, YB-1, and the ${\mathrm{m}}^6$${\mathrm{m}}^6$m^(6)\mathrm{m}^{6} A regulators.
小分子抑制剂是迄今为止最常见的 RBP 靶向策略，可在癌症进展过程中限制 RBP 的功能。然而，尽管有大量的 RBPs 与癌症和转移有关，但目前针对少数 RBPs 开发出的具有治疗潜力的小分子药物数量有限。这可能是因为大多数 RBPs 都被认为是 "不可药用 "的，因为它们缺乏传统的口袋或功能表位，而这些在经典酶和膜蛋白中经常可以找到 [224]。除此之外，化合物筛选方法仍然存在一些局限性和困难[225]。无论如何，针对在癌症和转移中具有明确作用的 RBPs（如 HuR、eIF4E、LIN28、MSI、YB-1 和 ${\mathrm{m}}^6$${\mathrm{m}}^6$m^(6)\mathrm{m}^{6} A 调节因子）筛选出了许多小分子化合物。

Emerging evidence suggests that abnormalities in the regulation and distribution of HuR play a role in the invasion and metastasis of a variety of human cancers [49-52] (Table 1). HuR is the most extensively characterized RBP in human cancers. HuR is comprised of three RRMs and a hinge region, and its activity is influenced in part by its cellular localization. Once activated, HuR can be translocated into the cytoplasm and interact with ARE in the $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTRs of target mRNAs, thus affecting the target mRNAs’ stability and translation [226,227]. Various small inhibitors have been identified that inhibit the nuclear/cytoplasmic translocation of HuR protein and its interaction with target RNAs. Considering that most molecules targeting HuR have been widely reviewed recently $[228,229]$$[228,229]$[228,229][228,229], we will concentrate on molecules that have been recently developed and molecules that are recognized as promising drugs for cancer metastasis. It is worth mentioning that KH-3 was recently identified as a small-molecule inhibitor of HuR, inhibiting EMT, migration, and invasion of pancreatic and breast cancer cells by disrupting the interaction of HuR with SNAI1 and FOXQ1 mRNAs [49, 171]. In addition, MS-444 is recognized as one of the most promising small-molecule drugs. By inhibiting HuR dimerization and translocation via binding to its RRM motifs, MS-444 exhibits anti-cancer effects in colorectal cancer, pancreatic cancer, and malignant glioma cells [230-232]. In addition, MS-444 inhibits cell invasion of glioblastoma
新的证据表明，HuR 的调控和分布异常在多种人类癌症的侵袭和转移中发挥作用 [49-52]（表 1）。HuR 是人类癌症中特征最广泛的 RBP。HuR 由三个 RRM 和一个铰链区组成，其活性部分受细胞定位的影响。一旦激活，HuR 可转位到细胞质中，并与靶 mRNA $3^{\prime }$$3^{\prime }$3^(')3^{\prime} UTR 中的 ARE 相互作用，从而影响靶 mRNA 的稳定性和翻译 [226,227]。目前已发现多种小型抑制剂可抑制 HuR 蛋白的核/胞质转位及其与靶 RNA 的相互作用。考虑到大多数靶向 HuR 的分子最近已被广泛综述 $[228,229]$$[228,229]$[228,229][228,229] ，我们将集中讨论最近开发的分子和被公认为有希望治疗癌症转移的分子。值得一提的是，KH-3 最近被确定为 HuR 的小分子抑制剂，它通过破坏 HuR 与 SNAI1 和 FOXQ1 mRNA 的相互作用，抑制胰腺癌和乳腺癌细胞的 EMT、迁移和侵袭 [49，171]。此外，MS-444 被认为是最有前途的小分子药物之一。MS-444 通过与其 RRM 基团结合抑制 HuR 的二聚化和转位，在结直肠癌、胰腺癌和恶性胶质瘤细胞中显示出抗癌作用 [230-232]。此外，MS-444 还能抑制胶质母细胞瘤细胞的侵袭[230-232]。
cells and brain tumor-initiating cells (BTICs) in vitro [232]. Furthermore, inhibition of HuR by MS-444 blocks MPNST cell growth and metastasis in vivo [51]. SRI-42127 was recently developed as one of a new class of molecules that inhibit HuR protein dimerization and thus growth inhibition in glioblastoma cells derived from patients. In comparison to MS-444, the SRI-42127 compound exhibited greater permeability across the blood-brain-barrier, increased potency against HuR dimerization, and ease of dissolution [233]. However, additional research is required to determine whether these compounds can be used to intervene in metastasis, especially in distal metastasis. Interestingly, Wang et al. found that uridine diphosphate-glucose (UDP-Glc) restricts lung cancer metastasis through inhibiting HuR binding to and stabilizing SNAI1 mRNA [81], implying that increasing UDP-Glc levels may be an effective way to inhibit cancer metastasis.
232]。此外，MS-444 对 HuR 的抑制可阻止 MPNST 细胞在体内的生长和转移 [51]。SRI-42127 是最近开发的一类新分子，可抑制 HuR 蛋白二聚化，从而抑制来自患者的胶质母细胞瘤细胞的生长。与 MS-444 相比，SRI-42127 化合物在血脑屏障中的渗透性更强，对 HuR 二聚化的抑制效力更高，而且易于溶解 [233]。然而，要确定这些化合物是否可用于干预转移，尤其是远端转移，还需要进行更多的研究。有趣的是，Wang 等人发现二磷酸尿苷-葡萄糖（UDP-Glc）通过抑制 HuR 与 SNAI1 mRNA 的结合和稳定 SNAI1 mRNA 限制了肺癌的转移[81]，这意味着增加 UDP-Glc 的水平可能是抑制癌症转移的有效方法。

LIN28/let-7 axis plays an important role in EMT and cancer metastasis $[28,93]$$[28,93]$[28,93][28,93] (Table 1). Martina et al. identified a small molecule, compound 1623, as an effective inhibitor targeting LIN28. Compound 1623 directly targets LIN28 and inhibits the interaction of LIN28 with pre-let-7, thereby attenuating the inhibition of let-7 maturation [234]. Recent evidence suggests that compound 1623 inhibits LIN28/let-7-mediated PD-L1 activation, leading to an enhancement of tumor immunity. In addition, compound 1623 exhibited an anti-migratory effect through repressing FAK activation and MMP9 expression in both cisplatin-resistant and non-resistant NSCLC cells, possibly due to inhibition of LIN28 [235]. The Borgelt group screened out a new class of small-molecule inhibitors, trisubstituted pyrrolinones, disrupting the LIN28-let-7 interaction. Compound C902, the most potent of the trisubstituted pyrrolinones, promotes let-7 maturation by entering the cold shock domain (CSD) of the LIN28 protein [236]. Recent research demonstrated that two compounds, GG-43 and GG-70, with a tricyclic tetrahydroquinoline (THQ)-containing scaffold derived from the Povarov reaction, are the most potent molecules that disrupt the LIN28-let-7 interaction by binding to the CSD of LIN28 [237]. A couple of additional LIN28 inhibitors, LI71 and TPEN, were identified using a fluorescence polarization (FP) assay [238]. LI71 is another YHQ-scaffold molecule with weak inhibition of LIN28 [237,238]. TPEN is in favor of disrupting the zinc-knuckle domain (ZKD) of LIN28, which attenuates the interaction between LIN28 and let-7 [238]. Given that LIN28 can interact with various miRNAs in addition to let-7, extra research is necessary to elucidate the mechanism underlying small-molecule drugs targeting LIN28.
LIN28/let-7轴在EMT和癌症转移中起着重要作用 $[28,93]$$[28,93]$[28,93][28,93] （表1）。Martina 等人发现了一种小分子化合物 1623，它是一种靶向 LIN28 的有效抑制剂。化合物 1623 直接靶向 LIN28，抑制 LIN28 与前 let-7 的相互作用，从而减弱对 let-7 成熟的抑制 [234]。最新证据表明，化合物 1623 可抑制 LIN28/let-7 介导的 PD-L1 激活，从而增强肿瘤免疫力。此外，化合物 1623 通过抑制顺铂耐药和非耐药 NSCLC 细胞中 FAK 的活化和 MMP9 的表达，表现出抗迁移作用，这可能是由于抑制了 LIN28 [235]。Borgelt 小组筛选出了一类新的小分子抑制剂--三取代吡咯烷酮，它能破坏 LIN28-let-7 的相互作用。化合物 C902 是三取代吡咯啉酮类化合物中最有效的一种，它通过进入 LIN28 蛋白的冷休克结构域（CSD）来促进 let-7 的成熟[236]。最近的研究表明，GG-43 和 GG-70 这两种化合物具有由 Povarov 反应衍生的含三环四氢喹啉 (THQ) 的支架，是通过与 LIN28 的 CSD 结合来破坏 LIN28-let-7 相互作用的最有效分子 [237]。利用荧光偏振（FP）测定法还发现了另外几种 LIN28 抑制剂 LI71 和 TPEN [238]。LI71 是另一种对 LIN28 有微弱抑制作用的 YHQ 支架分子 [237,238]。TPEN有利于破坏LIN28的锌-扣结构域（ZKD），从而减弱LIN28与let-7之间的相互作用[238]。鉴于 LIN28 除了能与 let-7 相互作用外，还能与多种 miRNA 相互作用，因此有必要开展更多研究，以阐明靶向 LIN28 的小分子药物的作用机制。

A growing body of studies examining the inhibition of eIF4E activity in multiple cancers has demonstrated a significant reduction of cell invasion and metastasis, along with suppression in cell proliferation in vitro and in vivo [196,202]. According to the cap-binding characteristics of eIF4E, ribavirin, a competitive inhibitor of the ${\mathrm{m}}^7\mathrm{G}$${\mathrm{m}}^7\mathrm{G}$m^(7)G\mathrm{m}^{7} \mathrm{G}-cap analog, was used as an anticancer therapeutic by targeting the eIF4E-mRNA interaction in multiple cancers [239]. Interestingly, ribavirin has a greater inhibitory effect on lung metastasis in a murine xenograft model of breast cancer, which is mechanistically due to inhibition of eIF4E, as well as EMT-related signaling pathways [240,241]. The anti-cancer/metastasis potential of ribavirin has led to phase I/II clinical trials to evaluate its efficacy in recurrent/metastatic HPV-related malignancies (NCT02308241, initiated but not recruiting yet), and other solid tumors (NCT01309490, completed pending results reported). 4Ei-1, a pro-drug that functions as an antagonist to the eIF4E-mRNA cap interaction, has been shown to enhance lung cancer cell chemosensitization to gemcitabine treatment [242], and to inhibit TGF- $\beta$$\beta$beta\beta-induced EMT in lung epithelial cells [243]. In addition, interfering with the interaction of the eIF4E with other factors involved in the assembly of the eIF4F complex, including eIF4A and eIF4G, is a promising strategy. Molecules such as 4EGI-1, 4E1RCat, and 4E2RCat are chemicals identified as inhibitors of the eIF4E-eIF4G interaction [196]. 4EGI-1 has been demonstrated to selectively inhibit the translation of mRNAs that encode proteins involved in CSC maintenance, angiogenesis, and metastasis [244].
越来越多的研究表明，抑制多种癌症中 eIF4E 的活性可显著减少细胞的侵袭和转移，同时抑制体外和体内细胞的增殖 [196,202]。根据 eIF4E 的帽结合特性，利巴韦林作为 ${\mathrm{m}}^7\mathrm{G}$${\mathrm{m}}^7\mathrm{G}$m^(7)G\mathrm{m}^{7} \mathrm{G} -cap 类似物的竞争性抑制剂，通过靶向 eIF4E 与多种癌症中的 MRNA 相互作用，被用作抗癌疗法 [239]。有趣的是，在乳腺癌小鼠异种移植模型中，利巴韦林对肺转移有更大的抑制作用，从机理上讲，这是由于抑制了 eIF4E 以及与 EMT 相关的信号通路 [240,241]。利巴韦林的抗癌/抗转移潜力促成了 I/II 期临床试验，以评估其对复发性/转移性 HPV 相关恶性肿瘤（NCT02308241，已启动但尚未招募）和其他实体瘤（NCT01309490，已完成，等待结果报告）的疗效。4Ei-1是一种能拮抗eIF4E-mRNA帽相互作用的原研药，已被证明能增强肺癌细胞对吉西他滨治疗的化疗敏感性[242]，并能抑制TGF- $\beta$$\beta$beta\beta 诱导的肺上皮细胞EMT[243]。此外，干扰 eIF4E 与参与 eIF4F 复合物组装的其他因子（包括 eIF4A 和 eIF4G）的相互作用也是一种很有前景的策略。4EGI-1、4E1RCat 和 4E2RCat 等分子是被确定为 eIF4E-eIF4G 相互作用抑制剂的化学物质 [196]。4EGI-1 已被证明可选择性地抑制编码参与 CSC 维持、血管生成和转移的蛋白质的 mRNA 的翻译 [244]。

MSIs are increasingly being implicated in metastasis and are associated with a poor prognosis in multiple cancers [54,61,245,246]. Using high-throughput screening from a library of $\sim 2000$$\sim 2000$∼2000\sim 2000 compounds, a fungal natural product, azaphilone-9 (Aza-9), was identified as an inhibitor of the MSI1/2-RNA interaction. In addition, liposomal Aza-9 improves Aza-9 entry into cells and inhibits the growth of colorectal cancer cells [247]. HuR was also identified as an Aza-9 target prior to MSI [248]. Other molecules, including oleic acid, (-)-gossypol, and Ro 08-2750 have proven to be inhibitors of MSI proteins, and their anti-cancer effects have been well-reviewed [203,249]. It remains unclear whether these molecules exert a significant suppressive effect on cancer metastasis.
MSIs 越来越多地与转移有关，并与多种癌症的不良预后有关 [54,61,245,246]。通过从 $\sim 2000$$\sim 2000$∼2000\sim 2000 化合物库中进行高通量筛选，一种真菌天然产物唑萘酮-9（Aza-9）被鉴定为 MSI1/2-RNA 相互作用的抑制剂。此外，脂质体 Aza-9 可提高 Aza-9 进入细胞的能力，抑制结直肠癌细胞的生长 [247]。在 MSI 之前，HuR 也被确定为 Aza-9 的靶点 [248]。包括油酸、(-)-gossypol 和 Ro 08-2750 在内的其他分子已被证明是 MSI 蛋白的抑制剂，它们的抗癌作用也得到了广泛的研究 [203,249]。目前还不清楚这些分子是否对癌症转移有明显的抑制作用。

It is now well established that YB-1 promotes EMT and metastasis at both transcriptional and post-transcriptional levels [250]. Fisetin, a natural product that acts as a potent inhibitor of the PI3K/AKT pathway, was found to inhibit YB-1 phosphorylation and EMT in prostate cancer cells. Mechanistically, fisetin binds to the CSD of YB-1, which blocks the phosphorylation of S102 by reducing its interaction with activated AKT [251]. Another small molecule inhibitor of YB-1, SU056, has been shown to repress ovarian cancer progression and function synergistically with paclitaxel in vivo [252]. Further investigation of SU056 into cancer metastasis is strongly recommended.
目前已经证实，YB-1 在转录和转录后水平上促进 EMT 和转移 [250]。研究发现，作为 PI3K/AKT 通路强效抑制剂的天然产物鱼腥草素能抑制前列腺癌细胞中的 YB-1 磷酸化和 EMT。从机理上讲，鱼藤素与 YB-1 的 CSD 结合，通过减少其与活化的 AKT 的相互作用来阻止 S102 的磷酸化 [251]。另一种 YB-1 小分子抑制剂 SU056 已被证明可抑制卵巢癌的进展，并在体内与紫杉醇协同发挥作用 [252]。强烈建议进一步研究 SU056 对癌症转移的作用。
$M^6$$M^6$M^(6)M^{6} A methylation has become an essential aspect in the regulation of carcinogenesis and tumor progression. Therefore, targeting the ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} regulator proteins is another promising therapeutic strategy. Chen et al. identified a small-molecule inhibitor, rhein, binding competitively to the RNA demethylase FTO [253]. Using a high-throughput FP assay, the Huang group identified meclofenamic acid (MA) as a specific inhibitor of FTO. MA competes with ${\mathrm{m}}^6$${\mathrm{m}}^6$m^(6)\mathrm{m}^{6} A-modified RNA to bind to FTO rather than ALKBH5 [254]. The same research group recently developed two potent FTO inhibitors, FB23 and FB23-2, which inhibit FTO demethylase activity by directly binding to FTO. Additionally, they found that FB23-2 significantly suppresses the proliferation and progression of acute myeloid leukemia (AML) cells in vivo, which mimics the effect of FTO depletion [255]. ALKBH5 is another $m^6\mathrm{A}$$m^6\mathrm{A}$m^(6)Am^{6} \mathrm{~A} demethylase that is believed to be oncogenic and metastatic in multiple cancers [256-258]. Two small-molecule inhibitors of ALKBH5, 2-[(1-hydroxy-2-oxo-2-phenylethyl)sulfanyl]acetic acid and 4-[(furan-2-yl)methyl]amino-1,2-dia-zinane-3,6-dione were identified through high-throughput screening of a library of 144000 compounds. The two compounds revealed a selective anti-proliferative effect in three leukemia cell lines, and a low or negligible effect in another leukemia cell line and a glioblastoma cell line [259]. Researchers developed an FP-based High-Throughput Methly Reading (HTMR) assay for screening molecules targeting DNA/RNA methyltransferases and demethylases that is homogeneous, simple, highly sensitive, and low-cost. Using the HTMR assay, they identified a promising known natural product, quercetin, that directly binds to the ALKBH5 catalytic domain [260]. Interestingly, ALKBH5 was found as an off-target for the molecule MV1035, which is a novel sodium channel blocker that has been tested on a few cancer cell lines. MV1035 directly inhibits ALKBH5-mediated CD73 protein expression, thereby attenuating glioblastoma cell migration and invasion [257], suggesting an anti-metastatic potential of MV1035. STM2457 was recently identified as a highly potent first-in-class catalytic inhibitor of methyltransferase METTL3. in an AML mouse model, treatment with STM2457 inhibits AML cell growth and prolongs survival [261].
$M^6$$M^6$M^(6)M^{6} A甲基化已成为调控癌变和肿瘤进展的一个重要方面。因此，靶向 ${\mathrm{m}}^6\mathrm{A}$${\mathrm{m}}^6\mathrm{A}$m^(6)A\mathrm{m}^{6} \mathrm{~A} 调节蛋白是另一种有前景的治疗策略。Chen 等人发现了一种小分子抑制剂 rhein，它能与 RNA 去甲基化酶 FTO 竞争性结合 [253]。利用高通量 FP 分析法，Huang 小组发现甲氯芬那酸（MA）是 FTO 的特异性抑制剂。MA与 ${\mathrm{m}}^6$${\mathrm{m}}^6$m^(6)\mathrm{m}^{6} A修饰的RNA竞争，与FTO而非ALKBH5结合 [254]。同一研究小组最近开发出了两种有效的 FTO 抑制剂 FB23 和 FB23-2，它们通过直接与 FTO 结合来抑制 FTO 去甲基化酶的活性。此外，他们还发现 FB23-2 能明显抑制急性髓性白血病（AML）细胞在体内的增殖和进展，这模拟了 FTO 去甲基化的效果 [255]。ALKBH5 是另一种 $m^6\mathrm{A}$$m^6\mathrm{A}$m^(6)Am^{6} \mathrm{~A} 去甲基化酶，据信在多种癌症中具有致癌和转移作用 [256-258]。通过对 144000 个化合物库进行高通量筛选，发现了 ALKBH5 的两种小分子抑制剂：2-[(1-羟基-2-氧代-2-苯基乙基)硫基]乙酸和 4-[(呋喃-2-基)甲基]氨基-1,2-二氮杂环庚烷-3,6-二酮。这两种化合物对三种白血病细胞株具有选择性抗增殖作用，而对另一种白血病细胞株和一种胶质母细胞瘤细胞株的作用较低或可以忽略不计 [259]。研究人员开发了一种基于 FP 的高通量甲基读数（HTMR）测定法，用于筛选 DNA/RNA 甲基转移酶和去甲基化酶的靶向分子，该测定法均匀、简单、灵敏度高且成本低。利用 HTMR 分析法，他们发现了一种很有前景的已知天然产物槲皮素，它能直接与 ALKBH5 催化结构域结合 [260]。 有趣的是，ALKBH5 被发现是 MV1035 分子的非靶点，MV1035 是一种新型钠通道阻滞剂，已在一些癌细胞系中进行了测试。MV1035 可直接抑制 ALKBH5 介导的 CD73 蛋白表达，从而减轻胶质母细胞瘤细胞的迁移和侵袭 [257]，这表明 MV1035 具有抗转移的潜力。在急性髓细胞性白血病小鼠模型中，STM2457 可抑制急性髓细胞性白血病细胞的生长并延长存活时间 [261]。

Given the limitation of small molecules to RBPs, it is a wise strategy to modulate mRNA or pre-mRNA encoding specific proteins. ASOs are chemically synthesized oligonucleotides that are approximately 12-30 nucleotides in length. They bind to target RNA based on Watson-Crick base pairing principles. ASOs are designed to exert different mechanisms in regulating target RNAs, such as RNase-H-mediated RNA destruction and translation blockade [262]. A second-generation ASO
鉴于小分子对 RBP 的限制，对编码特定蛋白质的 mRNA 或前 mRNA 进行调节是一种明智的策略。ASO 是化学合成的寡核苷酸，长度约为 12-30 个核苷酸。它们根据沃森-克里克碱基配对原则与目标 RNA 结合。ASO 的设计旨在发挥不同的机制来调节靶 RNA，如 RNase-H 介导的 RNA 破坏和翻译阻断 [262]。第二代 ASO
for eIF4E (4EASO) was shown to significantly suppress tumor growth in breast and prostate mouse models, with downregulated eIF4E protein levels [263]. 4EASO also inhibited cell proliferation in mesothelioma and NSCLC cells [264,265]. The effective pre-clinical results led to a series of phase I/II clinical trials. The result of a phase I trial (NCT00903708) in advanced cancer was reported, showing that 4EASO (LY2275796) treatment alone in advanced cancer did not show tumor response despite reduced eIF4E expression [266]. A phase I/II trial of combination chemotherapy in solid tumors and irinotecan-refractory colorectal cancer has also been completed and results are reported [262] (NCT01675128). However, the combination of 4EASO (ISIS 183750) with irinotecan did not lead to an objective response. Two additional phase I/II trials for ISIS 183750 in combination with multiple chemotherapeutics in castrate-resistant prostate cancer and NSCLC have been completed recently pending results (NCT01234025 and NCT01234038). In addition, several studies have shown that ASOs are potential therapeutics by targeting distinct RBPs, including hnRNPM, MSI, and YB-1 [267-269]. However, little research has been conducted to determine whether ASOs are involved in cancer metastasis, which is a critical point of intervention for cancer progression and recurrence.
在乳腺癌和前列腺癌小鼠模型中，eIF4E 蛋白水平下调后，4EASO 可显著抑制肿瘤生长 [263]。4EASO 还能抑制间皮瘤和 NSCLC 细胞的增殖 [264,265]。有效的临床前研究结果促成了一系列 I/II 期临床试验。一项针对晚期癌症的 I 期试验（NCT00903708）结果显示，尽管 eIF4E 表达减少，但晚期癌症患者单独使用 4EASO (LY2275796)治疗并未出现肿瘤反应 [266]。一项针对实体瘤和伊立替康难治性结直肠癌的联合化疗 I/II 期试验也已完成，并报告了结果[262]（NCT01675128）。然而，4EASO（ISIS 183750）与伊立替康的联合治疗并未产生客观反应。ISIS 183750 与多种化疗药物联合治疗阉割耐药前列腺癌和 NSCLC 的另外两项 I/II 期试验已于近期完成，正在等待结果（NCT01234025 和 NCT01234038）。此外，一些研究表明，ASOs 是针对不同 RBPs（包括 hnRNPM、MSI 和 YB-1）的潜在治疗药物 [267-269]。然而，关于 ASO 是否参与癌症转移的研究还很少，而癌症转移是癌症进展和复发的关键干预点。

Additionally, targeted RBP therapy based on siRNAs has demonstrated effectiveness and clinical safety, seeking to establish it as a clinically advanced RNA drug platform [270-272]. A siRNA against HuR therapy was developed and successfully reduced metastasis in a mouse model using a liposome nanoparticle delivery system [273].
此外，基于 siRNA 的 RBP 靶向治疗已证明有效且具有临床安全性，并试图将其确立为临床上先进的 RNA 药物平台 [270-272]。一种针对 HuR 的 siRNA疗法已被开发出来，并利用脂质体纳米颗粒递送系统在小鼠模型中成功减少了转移[273]。

Proteolysis-targeting chimera (PROTAC) has emerged as a precise and effective technique for target protein degradation. A PROTAC molecule is composed of three components, including a target-binding ligand for the protein of interest (POI), a ligand for recruiting an E3 ubiquitin ligase, and a linker structure that covalently links the two functional ligands together [274]. The ligand of POI is usually a small molecule responsible only for the attachment to its POI, which is subjected to proteasome-mediated degradation by the E3 ligase-recruiting ligand (Fig. 5). Therefore, this PROTAC-strategy makes it possible to target those “undruggable” proteins (e.g., RBPs) to accomplish tasks that traditional small-molecule drugs could not complete before. To date, there are few reports on conventional PROTAC for RBPs because screening of small-molecule-based target ligand of PROTAC for RBPs is still difficult. Recently, Ghidini et al. developed an improved PROTAC, termed RNA-PROTAC, that selectively destructs the RBP [275]. They designed a structurally modified 7nt-oligonucleotide, which is identical to the RNA consensus binding element (RBE) sequence of LIN28A and acts as a ligand for POI. The RNA-PROTAC selectively binds to LIN28A and inhibits LIN28A protein levels in cancer cells (Fig. 5). This proof-of-concept of RNA-PROTAC provides a promising therapeutic approach for targeted inhibition of RBPs.
蛋白水解靶向嵌合体（PROTAC）是一种精确有效的靶蛋白降解技术。一个 PROTAC 分子由三部分组成，包括一个目标蛋白结合配体（POI）、一个用于招募 E3 泛素连接酶的配体以及一个将两个功能配体共价连接在一起的连接体结构 [274]。POI 的配体通常是一种小分子，只负责附着在其 POI 上，而 POI 则被 E3 配体酶招募配体介导的蛋白酶体降解（图 5）。因此，这种 PROTAC 策略可以靶向那些 "不可药用 "的蛋白质（如 RBPs），完成传统小分子药物无法完成的任务。迄今为止，有关传统 PROTAC 用于 RBPs 的报道还很少，因为筛选基于小分子的 PROTAC 用于 RBPs 的靶配体还很困难。最近，Ghidini 等人开发了一种改进的 PROTAC，称为 RNA-PROTAC，可选择性地破坏 RBP [275]。他们设计了一种结构上经过修饰的 7nt 寡核苷酸，该寡核苷酸与 LIN28A 的 RNA 共识结合元件（RBE）序列相同，可作为 POI 的配体。RNA-PROTAC 可选择性地与 LIN28A 结合，抑制癌细胞中的 LIN28A 蛋白水平（图 5）。RNA-PROTAC 的这一概念证明为靶向抑制 RBPs 提供了一种很有前景的治疗方法。

In addition, therapeutic synthetic peptides, commonly composed of less than 55 amino acids, are garnering increasing attention for biomedical applications as they are easier to synthesize and show higher specificity and lower immunogenicity [276-278]. With respect to ovarian cancer, synthetic small peptides targeting elF4E have been developed and shown to have strong antitumor effects in animal models [279]. Although being less used, aptamers represent another RBP-targeting strategy applied in cancer treatment. Only two therapeutic aptamers are undergoing clinical trials for cancer treatment [280]. Notably, the emerging potential treatment strategies (e.g., circRNAs-based) have been gradually valued and considered by researchers. CircRHOBTB3 has been shown to suppress metastasis by regulating the HuR/PTBP1 axis in colorectal cancer [173]. However, there is no clue that circRNAs-RBPs-based therapeutics designed for
此外，治疗性合成肽通常由少于 55 个氨基酸组成，由于更容易合成、特异性更强、免疫原性更低，因此在生物医学应用中越来越受到关注 [276-278]。在卵巢癌方面，针对 elF4E 的合成小肽已被开发出来，并在动物模型中显示出很强的抗肿瘤效果 [279]。虽然使用较少，但适配体是另一种应用于癌症治疗的 RBP 靶向策略。目前只有两种治疗性适配体正在进行癌症治疗的临床试验[280]。值得注意的是，新兴的潜在治疗策略（如基于 circRNAs 的治疗策略）已逐渐受到研究人员的重视和考虑。有研究表明，CircRHOBTB3 可通过调节 HuR/PTBP1 轴抑制结直肠癌的转移 [173]。然而，目前尚无线索表明基于 circRNAs-RBPs 的疗法可用于
cancer treatment are undergoing clinical trials, but this picture is beginning to change. CRISPR/Cas9 is currently being employed in cancer molecular biology and oncology to execute powerful specific gene editing, rendering it more valuable for biological and therapeutic applications [281]. Evidence indicates that deleting HuR via the CRISPR/Cas9 technology suppresses EMT and metastasis in pancreatic cancer [171]. However, before fully elucidating the mechanisms underlying RBP-mediated cancer metastasis, it is still challenging to determine the best therapeutic intervention to deliver the greatest therapeutic effect on patients.
但这种情况正在开始改变。目前，CRISPR/Cas9 正被用于癌症分子生物学和肿瘤学，以执行强大的特异性基因编辑，使其在生物和治疗应用方面更具价值 [281]。有证据表明，通过 CRISPR/Cas9 技术删除 HuR 可抑制胰腺癌的 EMT 和转移 [171]。然而，在完全阐明 RBP 介导癌症转移的机制之前，确定最佳治疗干预措施以对患者产生最大疗效仍具有挑战性。

This review provides an overview of the biological mechanisms of RBPs involved in cancer metastasis and highlights the prospect of RBPtargeted therapeutics for cancer metastasis. It has been well-known that RBPs regulate the expression of downstream genes associated with proor anti-metastasis factors in all aspects of RNA biology, underscoring the importance of RBPs in cancer metastasis. With the development of deepsequencing technology, including single-cell sequencing and crosslinked immunoprecipitation (CLIP) analysis, more and more cancerassociated RBPs and their targets have been discovered and subjected to functional and mechanistic studies [5]. However, it is a great challenge for researchers to identify cancer metastasis-specific RBPs and their targets, as well as to elucidate the complex regulatory network centered on RBPs [2]. Moreover, because the function of a considerable number of RBPs has not been fully understood, our current understanding of cancer metastasis-specific RBPs seems to be only the tip of the iceberg, which has become an urgent problem for basic and clinical researchers. Another major challenge is developing and employing an efficient and reliable biological evaluation system covering cellular and animal metastasis models and convenient data analysis software for investigating those screened RBPs. A commonly used mouse model of breast cancer metastasis has been established by using a lung metastatic cell line derived from the parental breast cancer cells. Based on this model, investigators of a research group developed multiple
这篇综述概述了 RBPs 参与癌症转移的生物学机制，并强调了针对癌症转移的 RBP 靶向疗法的前景。众所周知，RBPs 在 RNA 生物学的各个方面调控与促转移或抗转移因子相关的下游基因的表达，凸显了 RBPs 在癌症转移中的重要性。随着包括单细胞测序和交联免疫沉淀（CLIP）分析在内的深度测序技术的发展，越来越多的癌症相关 RBPs 及其靶标被发现并进行了功能和机理研究 [5]。然而，对于研究人员来说，确定癌症转移特异性 RBPs 及其靶标，以及阐明以 RBPs 为中心的复杂调控网络是一个巨大的挑战 [2]。此外，由于相当多的 RBPs 的功能尚未被完全了解，我们目前对癌症转移特异性 RBPs 的了解似乎只是冰山一角，这已成为基础和临床研究人员亟待解决的问题。另一个重大挑战是开发和使用高效可靠的生物评估系统，涵盖细胞和动物转移模型，以及方便的数据分析软件来研究这些筛选出的 RBPs。常用的乳腺癌转移小鼠模型是通过使用源自亲代乳腺癌细胞的肺转移细胞系建立的。在此模型的基础上，一个研究小组的研究人员开发了多个
computational algorithms for identifying specific structural RNA cis-elements responsible for AS and RNA stability, as well as predicting their RNA-binding trans-factors involved in metastasis [80,140]. This raises the possibility of therapeutic intervention in cancer metastasis by inhibiting interactions between such trans-factors and RNA cis-elements with ASO-strategies or small molecules. Subsequently, how to integrate and analyze the massive data to reveal the mechanisms of the complicated and fine RBP-based regulatory network in cancer metastasis will be challenging.
计算算法可用于识别负责 AS 和 RNA 稳定性的特定结构 RNA 顺式元件，并预测其参与转移的 RNA 结合反式因子 [80,140]。这就为通过 ASO 策略或小分子抑制这些反式因子与 RNA 顺式元件之间的相互作用，从而对癌症转移进行治疗干预提供了可能。随后，如何整合和分析海量数据以揭示癌症转移中复杂而精细的基于 RBP 的调控网络的机制将是一项挑战。

The canonical RBPs commonly recognize and interact with their RNA targets by forming RNP complexes via their RBDs. It is well established that RBP does not work alone, but rather collaborates with other RBPs or protein factors to form functional complexes that perform specific functions [282]. Furthermore, numerous lncRNAs and circRNAs interact with RBPs, influencing the formation, stability, and function of these complexes. As a result, we believe that future studies should focus on the patterns of protein-RNA-protein interactions, as well as the dynamic changes and functions of these interactions during tumor metastasis. At the same time, RBP drug strategies necessitate a greater focus on targeting those RBP-RNA-RBP complexes. As RNAs interact with RBP via their unique cis-elements, using antisense nucleic acids to antagonize the target RNA-RBP complex could be a simple and efficient therapeutic strategy in the future. RBP has a broad range of effects due to the diversity and complexity of the RNAs involved in RBP binding, albeit it is not as powerful as many kinases and receptors that play a dominant role in cancer development and metastasis. As a result, it appears that RBP regulation is a secondary fine turning centered on the dominant function of those kinases and receptors. Therefore, researchers need to comprehensively understand RBPs and strengthen the development of an RBP-targeting therapeutic strategy. Furthermore, RBP inhibitors in combination with other targeted drugs (such as tyrosine kinase inhibitors) might be a promising therapeutic option for tumor metastasis and recurrence. Nonetheless, there are some old problems to be solved, such as: (1) the “drug” delivery system of RBP targeted therapy needs to be continuously improved; (2) better biochemical modifications should be explored to grant RBP targeted “drugs” the best stability, safety,
典型的 RBP 通常通过其 RBD 形成 RNP 复合物，从而识别 RNA 靶标并与其相互作用。已经证实，RBP 并非单独工作，而是与其他 RBP 或蛋白因子合作形成功能复合物，执行特定功能 [282]。此外，许多 lncRNA 和 circRNA 与 RBPs 相互作用，影响这些复合物的形成、稳定性和功能。因此，我们认为未来的研究应关注蛋白质-RNA-蛋白质相互作用的模式，以及这些相互作用在肿瘤转移过程中的动态变化和功能。与此同时，RBP 药物策略必须更加关注靶向那些 RBP-RNA-RBP 复合物。由于 RNA 通过其独特的顺式元件与 RBP 相互作用，使用反义核酸来拮抗目标 RNA-RBP 复合物可能是未来一种简单而有效的治疗策略。由于参与 RBP 结合的 RNA 的多样性和复杂性，RBP 具有广泛的作用，尽管它不如许多在癌症发展和转移中起主导作用的激酶和受体那么强大。因此，RBP 的调控似乎是以这些激酶和受体的主导功能为中心的次要微调。因此，研究人员需要全面了解 RBP，并加强 RBP 靶向治疗策略的开发。此外，RBP 抑制剂与其他靶向药物（如酪氨酸激酶抑制剂）联用可能是治疗肿瘤转移和复发的一种有前景的选择。 尽管如此，仍有一些老问题亟待解决，例如(1) RBP 靶向治疗的 "药物 "输送系统需要不断改进；(2) 应探索更好的生化修饰方法，以赋予 RBP 靶向 "药物 "最佳的稳定性和安全性、

Fig. 5. PROTAC and RNA-PROTAC interact with RBPs, enabling them to be degraded by the proteasome. BioRender (https://biorender.com) was used to create the image.
图 5.PROTAC 和 RNA-PROTAC 与 RBPs 相互作用，使它们能够被蛋白酶体降解。使用 BioRender ( https://biorender.com) 绘制图像。
targeted distribution, and long-lasting effect. Fortunately, since abnormal RBP expression and dysfunction have been widely reported in human cancer metastasis, these metastasis-associated RBPs are increasingly being evaluated and are expected to be used as clinical diagnostic and prognostic indicators. Despite the challenges of developing RBP-based therapeutic strategies, we believe that a new RBP-targeting therapeutic era for cancer metastasis is on the horizon.
RBP 具有靶向分布和持久作用的特点。幸运的是，由于在人类癌症转移中广泛报道了 RBP 的异常表达和功能障碍，这些与转移相关的 RBP 正越来越多地被评估，并有望被用作临床诊断和预后指标。尽管开发基于 RBP 的治疗策略面临诸多挑战，但我们相信，一个针对癌症转移的新 RBP 靶向治疗时代即将到来。

This work was supported in part by the grants from National Natural Science Foundation of China (82073198, 81872343, 81972174), and Suzhou Key Laboratory for Molecular Cancer Genetics (SZS201209), and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD).
本研究部分受到国家自然科学基金（82073198、81872343、81972174）、苏州市肿瘤分子遗传学重点实验室（SZS201209）和江苏省高等学校重点学科建设资助项目（PAPD）的资助。

The authors declare that there are no conflicts of interest.
作者声明不存在利益冲突。

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