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Abstract：
Increasing evidence indicates that c-mesenchymal-epithelial transition factor (cMET) plays an important role in the malignant progression of colorectal cancer (CRC). However, the underlying mechanism is not fully understood. As a metastasis suppressor, raf kinase inhibitory protein (RKIP) loss has been reported in many cancer types. In this study, the expression levels of cMET and RKIP in CRC tissues and cell lines were determined, and their crosstalk and potential biological effects were explored in vitro and in vivo. Our results showed that cMET was inversely correlated with RKIP. Both cMET upregulation and RKIP downregulation indicated poor clinical outcomes. Moreover, the MAPK/ERK signaling pathway was implicated in the regulation of cMET and RKIP. Overexpression of cMET promoted tumor cell epithelial-mesenchymal transition, invasion, migration, and chemoresistance, whereas the effects could be efficiently inhibited by increased RKIP. Notably, small hairpin RNA-mediated cMET knockdown dramatically suppressed cell proliferation, although no RKIP-induced influence on cell growth was observed in CRC. Altogether, cMET overexpression may contribute to tumor progression by inhibiting the antioncogene RKIP, providing preclinical justification for targeting RKIP to treat cMET-induced metastasis of CRC.
摘要：
越来越多的证据表明，c-间质上皮转化因子（cMET）在结直肠癌（CRC）的恶性进展中起着重要作用。然而,潜在的机制还没有完全理解。作为转移抑制剂，在许多癌症类型中已经报道了raf激酶抑制蛋白(RKIP)丢失。在这项研究中,测定CRC组织和细胞系中cMET和RKIP的表达水平,并在体外和体内探索了它们的串扰和潜在的生物学效应。我们的结果表明cMET与RKIP呈负相关。cMET上调和RKIP下调均表明临床结果较差。此外，MAPK/ERK信号通路参与cMET和RKIP的调节。cMET过表达促进肿瘤细胞上皮-间质转化,入侵,迁移,和化学抗性，而RKIP的增加可以有效抑制这些影响。值得注意的是,小发夹RNA介导的cMET敲低可显著抑制细胞增殖，尽管在CRC中未观察到RKIP对细胞生长的影响。总之,cMET过表达可能通过抑制抗癌基因RKIP促进肿瘤进展，为靶向RKIP治疗cMET诱导的CRC转移提供临床前理由。
