Cessna Hannah, Baritaki Stavroula, Zaravinos Apostolos, Bonavida Benjamin
Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, CA 90095, USA.
Laboratory of Experimental Oncology, Division of Surgery, School of Medicine, University of Crete, 71003 Heraklion, Greece.
Cancers (Basel). 2022 Sep 22;14(19):4596. doi: 10.3390/cancers14194596.
The Raf Kinase Inhibitor Protein (RKIP) is a unique gene product that directly inhibits the Raf/Mek/Erk and NF-kB pathways in cancer cells and resulting in the inhibition of cell proliferation, viability, EMT, and metastasis. Additionally, RKIP is involved in the regulation of cancer cell resistance to both chemotherapy and immunotherapy. The low expression of RKIP expression in many cancer types is responsible, in part, for the pathogenesis of cancer and its multiple properties. The inhibition of EMT and metastasis by RKIP led to its classification as a tumor suppressor. However, the mechanism by which RKIP mediates its inhibitory effects on EMT and metastases was not clear. We have proposed that one mechanism involves the negative regulation by RKIP of the expression of various gene products that mediate the mesenchymal phenotype as well as the positive regulation of gene products that mediate the epithelial phenotype via signaling cross talks between RKIP and each gene product. We examined several EMT mesenchymal gene products such as Snail, vimentin, N-cadherin, laminin and EPCAM and epithelial gene products such as E-cadherin and laminin. We have found that indeed these negative and positive correlations were detected in the signaling cross-talks. In addition, we have also examined bioinformatic data sets on different human cancers and the findings corroborated, in large part, the findings observed in the signaling cross-talks with few exceptions in some cancer types. The overall findings support the underlying mechanism by which the tumor suppressor RKIP regulates the expression of gene products involved in EMT and metastasis. Hence, the development of agent that can selectively induce RKIP expression in cancers with low expressions should result in the activation of the pleiotropic anti-cancer activities of RKIP and resulting in multiple effects including inhibition of tumor cell proliferation, EMT, metastasis and sensitization of resistant tumor cells to respond to both chemotherapeutics and immunotherapeutics.
Raf激酶抑制蛋白（RKIP）是一种独特的基因产物，它直接抑制癌细胞中的Raf/Mek/Erk和NF-κB信号通路，从而抑制细胞增殖、活力、上皮-间质转化（EMT）和转移。此外，RKIP还参与调节癌细胞对化疗和免疫疗法的抗性。许多癌症类型中RKIP表达的降低在一定程度上导致了癌症的发病机制及其多种特性。RKIP对EMT和转移的抑制作用使其被归类为肿瘤抑制因子。然而，RKIP介导其对EMT和转移抑制作用的机制尚不清楚。我们提出一种机制涉及RKIP对介导间充质表型的各种基因产物表达的负调控，以及通过RKIP与每个基因产物之间的信号串扰对介导上皮表型的基因产物的正调控。我们检测了几种EMT间充质基因产物，如Snail、波形蛋白、N-钙黏蛋白、层粘连蛋白和EPCAM，以及上皮基因产物，如E-钙黏蛋白和层粘连蛋白。我们发现，在信号串扰中确实检测到了这些负相关和正相关。此外，我们还研究了不同人类癌症的生物信息数据集，其结果在很大程度上证实了在信号串扰中观察到的结果，在某些癌症类型中仅有少数例外。总体研究结果支持了肿瘤抑制因子RKIP调节参与EMT和转移的基因产物表达的潜在机制。因此，开发能够在低表达癌症中选择性诱导RKIP表达的药物，应能激活RKIP的多效抗癌活性，并产生多种效应，包括抑制肿瘤细胞增殖、EMT、转移以及使耐药肿瘤细胞对化疗药物和免疫治疗药物敏感。
Zotero 插件
