Lee SoHyun, Wottrich Stephanie, Bonavida Benjamin
Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, USA.
Tumour Biol. 2017 Apr;39(4):1010428317692253. doi: 10.1177/1010428317692253.
Raf-kinase inhibitor protein has been reported to inhibit both the Raf/mitogen extracellular signal-regulated kinase/extracellular signal-regulated kinase and nuclear factor kappa-light-chain of activated B cells pathways. It has also been reported in cancers that Raf-kinase inhibitor protein behaves as a metastatic suppressor as well as a chemo-immunosensitizing factor to drug/immune-mediated apoptosis. The majority of cancers exhibit low or no levels of Raf-kinase inhibitor protein. Hence, the activities of Raf-kinase inhibitor protein contrast, in part, to those mediated by several cancer stem cell transcription factors for their roles in resistance and metastasis. In this review, the existence of crosstalks in the signaling pathways between Raf-kinase inhibitor protein and several cancer stem cell transcription factors (Oct4, KLF4, Sox2 and Nanog) was assembled. Oct4 is induced by Lin28, and Raf-kinase inhibitor protein inhibits the microRNA binding protein Lin28. The expression of Raf-kinase inhibitor protein inversely correlates with the expression of Oct4. KLF4 does not interact directly with Raf-kinase inhibitor protein, but rather interacts indirectly via Raf-kinase inhibitor protein's regulation of the Oct4/Sox2/KLF4 complex through the mitogen-activated protein kinase pathway. The mechanism by which Raf-kinase inhibitor protein inhibits Sox2 is via the inhibition of the mitogen-activated protein kinase pathway by Raf-kinase inhibitor protein. Thus, Raf-kinase inhibitor protein's relationship with Sox2 is via its regulation of Oct4. Inhibition of extracellular signal-regulated kinase by Raf-kinase inhibitor protein results in the upregulation of Nanog. The inhibition of Oct4 by Raf-kinase inhibitor protein results in the failure of the heterodimer formation of Oct4 and Sox2 that is necessary to bind to the Nanog promoter for the transcription of Nanog. The findings revealed that there exists a direct correlation between the expression of Raf-kinase inhibitor protein and the expression of each of the above transcription factors. Based on these analyses, we suggest that the expression level of Raf-kinase inhibitor protein may be involved in the regulation of the cancer stem cell phenotype.
据报道，Raf激酶抑制蛋白可抑制Raf/丝裂原细胞外信号调节激酶/细胞外信号调节激酶和活化B细胞核因子κ轻链通路。在癌症中也有报道称，Raf激酶抑制蛋白可作为转移抑制因子以及药物/免疫介导凋亡的化学免疫增敏因子。大多数癌症中Raf激酶抑制蛋白水平较低或无表达。因此，Raf激酶抑制蛋白的活性在一定程度上与几种癌症干细胞转录因子介导的活性相反，因为它们在耐药性和转移中发挥作用。在本综述中，汇总了Raf激酶抑制蛋白与几种癌症干细胞转录因子（Oct4、KLF4、Sox2和Nanog）信号通路中的相互作用。Oct4由Lin28诱导，而Raf激酶抑制蛋白抑制微小RNA结合蛋白Lin28。Raf激酶抑制蛋白的表达与Oct4的表达呈负相关。KLF4不直接与Raf激酶抑制蛋白相互作用，而是通过Raf激酶抑制蛋白通过丝裂原活化蛋白激酶途径对Oct4/Sox2/KLF4复合物的调节间接相互作用。Raf激酶抑制蛋白抑制Sox2的机制是通过Raf激酶抑制蛋白对丝裂原活化蛋白激酶途径的抑制。因此，Raf激酶抑制蛋白与Sox2的关系是通过其对Oct4的调节。Raf激酶抑制蛋白对细胞外信号调节激酶的抑制导致Nanog上调。Raf激酶抑制蛋白对Oct4的抑制导致Oct4和Sox2异二聚体形成失败，而Oct4和Sox2异二聚体形成是结合Nanog启动子进行Nanog转录所必需的。研究结果表明，Raf激酶抑制蛋白的表达与上述每个转录因子的表达之间存在直接相关性。基于这些分析，我们认为Raf激酶抑制蛋白的表达水平可能参与癌症干细胞表型的调节。
