RNA-binding proteins (RBPs) play fundamental roles in cancer; however, we still lack knowledge about to what extent RBPs are dysregulated, as well as about perturbed signaling pathways in cancer. In this study, we integrated analysis of multidimensional data across >10,000 cancer patients and >1,000 cell lines. We identified a top candidate RBP: eukaryotic translation initiation factor 2 subunit beta (EIF2S2). EIF2S2 is highly expressed in tumors and is associated with malignant features as well as patient prognosis. Functional assays performed in cancer cells revealed that EIF2S2 promotes cancer cell proliferation, migration, and invasion in vitro as well as tumor growth and metastasis in vivo. Mechanistic investigations further demonstrated that EIF2S2 promotes tumorigenesis and progression by directly binding to a long non-coding RNA, LINC01600, which physically interacts with the MYC protein and increases its stability. Interestingly, we revealed that the EIF2S2-LINC01600-MYC axis can activate the Wnt/β-catenin pathway by inhibiting the activity of FHIT-related enhancers and FHIT expression. Finally, EIF2S2 knockdown combined with oxaliplatin treatment could be a potential combination therapy in cancer. Our integrated analysis provided detailed knowledge of the function of the EIF2S2-LINC01600-MYC axis, which will facilitate the development of rational combination therapies for cancer.

中文翻译：

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RBP EIF2S2通过调节经由FHIT相关增强剂的MYC介导的抑制作用来促进肿瘤发生和进展。

RNA结合蛋白（RBP）在癌症中起着基本作用。但是，我们仍然缺乏关于RBP失调的程度以及癌症中受干扰的信号通路的知识。在这项研究中，我们对超过10,000名癌症患者和1,000多个细胞系的多维数据进行了综合分析。我们确定了一个最高的候选RBP：真核翻译起始因子2亚基beta（EIF2S2）。EIF2S2在肿瘤中高表达，并与恶性特征以及患者预后相关。在癌细胞中进行的功能分析表明，EIF2S2在体外促进癌细胞的增殖，迁移和侵袭，并在体内促进肿瘤的生长和转移。机制研究进一步表明，EIF2S2通过直接结合长的非编码RNA来促进肿瘤发生和发展，LINC01600，它与MYC蛋白发生物理相互作用并增加其稳定性。有趣的是，我们揭示了EIF2S2-LINC01600-MYC轴可以通过抑制FHIT相关增强子的活性和FHIT表达来激活Wnt /β-catenin途径。最后，EIF2S2组合式联合奥沙利铂治疗可能是潜在的癌症联合治疗。我们的综合分析提供了EIF2S2-LINC01600-MYC轴功能的详细知识，这将有助于开发合理的癌症联合疗法。EIF2S2组合式联合奥沙利铂治疗可能是一种潜在的癌症联合治疗。我们的综合分析提供了EIF2S2-LINC01600-MYC轴功能的详细知识，这将有助于开发合理的癌症联合疗法。EIF2S2组合式联合奥沙利铂治疗可能是一种潜在的癌症联合治疗。我们的综合分析提供了EIF2S2-LINC01600-MYC轴功能的详细知识，这将有助于开发合理的癌症联合疗法。