Untreated primary carcinomas often lead to progression, invasion and metastasis, a process that involves the epithelial-to-mesenchymal transition (EMT). Several transcription factors (TFs) mediate the development of EMT, including SNAIL1/SNAIL2, TWIST1/TWIST2 and ZEB1/ZEB2, which are overexpressed in various carcinomas along with the under expression of the metastasis suppressor Raf Kinase Inhibitor Protein (RKIP). Overexpression of RKIP inhibits EMT and the above associated TFs. We, therefore, hypothesized that there are inhibitory cross-talk signaling pathways between RKIP and these TFs. Accordingly, we analyzed the various properties and biomarkers associated with the epithelial and mesenchymal tissues and the various molecular signaling pathways that trigger the EMT phenotype such as the TGF-β, the RTK and the Wnt pathways. We also presented the various functions and the transcriptional, post-transcriptional and epigenetic regulations for the expression of each of the EMT TFs. Likewise, we describe the transcriptional, post-transcriptional and epigenetic regulations of RKIP expression. Various signaling pathways mediated by RKIP, including the Raf/MEK/ERK pathway, inhibit the TFs associated with EMT and the stabilization of epithelial E-Cadherin expression. The inverse relationship between RKIP and the TF expressions and the cross-talks were further analyzed by bioinformatic analysis. High mRNA levels of RKIP correlated negatively with those of SNAIL1, SNAIL2, TWIST1, TWIST2, ZEB1, and ZEB2 in several but not all carcinomas. However, in these carcinomas, high levels of RKIP were associated with good prognosis, whereas high levels of the above transcription factors were associated with poor prognosis. Based on the inverse relationship between RKIP and EMT TFs, it is postulated that the expression level of RKIP in various carcinomas is clinically relevant as both a prognostic and diagnostic biomarker. In addition, targeting RKIP induction by agonists, gene therapy and immunotherapy will result not only in the inhibition of EMT and metastases in carcinomas, but also in the inhibition of tumor growth and reversal of resistance to various therapeutic strategies. However, such targeting strategies must be better investigated as a result of tumor heterogeneities and inherent resistance and should be better adapted as personalized medicine.
未经治疗的原发性癌常导致进展、侵袭和转移，这一过程涉及上皮-间质转化（EMT）。多种转录因子（TFs）介导EMT的发生发展，包括SNAIL1/SNAIL2、TWIST1/TWIST2和ZEB1/ZEB2，这些因子在多种癌症中过表达，同时转移抑制因子Raf激酶抑制蛋白（RKIP）表达下调。RKIP的过表达可抑制EMT及上述相关转录因子。因此，我们推测RKIP与这些转录因子之间存在抑制性交互信号通路。基于此，我们分析了与上皮组织和间质组织相关的多种特性及生物标志物，以及触发EMT表型的多种分子信号通路，如TGF-β通路、RTK通路和Wnt通路。同时阐述了各EMT转录因子的功能及其在转录、转录后和表观遗传层面的调控机制。相应地，我们也描述了RKIP表达的转录、转录后及表观遗传调控机制。RKIP介导的多种信号通路（包括Raf/MEK/ERK通路）可抑制EMT相关转录因子并稳定上皮性E-钙黏蛋白的表达。通过生物信息学分析进一步验证了RKIP与转录因子表达之间的负相关关系及其交互作用。在部分（非全部）癌症中，RKIP的高mRNA水平与SNAIL1、SNAIL2、TWIST1、TWIST2、ZEB1和ZEB2呈负相关。值得注意的是，在这些癌症中，RKIP高表达与良好预后相关，而上述转录因子高表达则与不良预后相关。基于RKIP与EMT转录因子间的负相关关系，我们认为多种癌症中RKIP的表达水平具有临床意义，可作为预后和诊断的生物标志物。此外，通过激动剂、基因疗法和免疫疗法靶向诱导RKIP表达，不仅能抑制癌症的EMT和转移进程，还可抑制肿瘤生长并逆转对多种治疗策略的耐药性。然而，由于肿瘤异质性和固有耐药性的存在，此类靶向策略需进一步深入研究，并应作为个体化医疗方案进行优化适配。
肿瘤(癌症)患者之家