Raf激酶抑制蛋白(RKIP)被认为是真正的肿瘤抑制基因,其表达减少或缺失与各种实体瘤的进展和不良预后有关。它通过调节不同的细胞内信号通路在致癌作用中发挥多方面的作用,包括那些由HER受体如MAPK控制的。鉴于HER受体过度表达在许多肿瘤类型中的意义,我们研究了实体瘤中RKIP和HER受体之间的潜在致癌关系.通过对30个TCGAPanCancerAtlas研究的全面计算机分析,包括实体瘤(10,719个样本),我们发现了令人信服的证据,即在30项研究中的25项实体瘤中,RKIP和EGFR表达呈负相关.相反,其他HER受体(ERBB2,ERBB3和ERBB4)呈显著正相关.特别是,宫颈癌(CC)作为一种在RKIP和EGFR表达之间表现出强烈负相关的肿瘤类型,这一发现在202例患者样本的队列中得到了进一步验证.随后的涉及EGFR和RKIP的药理学和遗传调节的体外实验表明,RKIP消耗导致EGFRmRNA水平的显着上调和EGFR磷酸化的诱导。相反,EGFR过度激活降低了CC细胞系中的RKIP表达。此外,我们在RKIP低和EGFR高表达的患者中发现了一个共同的分子特征,并证明了这种负相关在CC患者中的预后价值.总之,我们的发现揭示了RKIP和EGFR在各种实体瘤中的表达之间的负相关,揭示了导致宫颈癌中与RKIP和EGFR相关的侵袭性表型的潜在分子机制。
Raf Kinase Inhibitor Protein (
RKIP) is recognized as a bona fide tumor suppressor gene, and its diminished expression or loss is associated with the progression and poor prognosis of various solid tumors. It exerts multifaceted roles in carcinogenesis by modulating diverse intracellular signaling pathways, including those governed by HER receptors such as MAPK. Given the significance of HER receptor overexpression in numerous tumor types, we investigated the potential oncogenic relationship between
RKIP and HER receptors in solid tumors. Through a comprehensive in silico analysis of 30 TCGA PanCancer Atlas studies encompassing solid tumors (10,719 samples), we uncovered compelling evidence of an inverse correlation between RKIP and EGFR expression in solid tumors observed in 25 out of 30 studies. Conversely, a predominantly positive association was noted for the other HER receptors (ERBB2, ERBB3, and ERBB4). In particular, cervical cancer (CC) emerged as a tumor type exhibiting a robust inverse association between RKIP and EGFR expression, a finding that was further validated in a cohort of 202 patient samples. Subsequent in vitro experiments involving pharmacological and genetic modulation of EGFR and
RKIP showed that RKIP depletion led to significant upregulation of EGFR mRNA levels and induction of EGFR phosphorylation. Conversely, EGFR overactivation decreased
RKIP expression in CC cell lines. Additionally, we identified a common molecular signature among patients depicting low
RKIP and high EGFR expression and demonstrated the prognostic value of this inverse correlation in CC patients. In conclusion, our findings reveal an inverse association between RKIP and EGFR expression across various solid tumors, shedding new light on the underlying molecular mechanisms contributing to the aggressive phenotype associated with RKIP and EGFR in cervical cancer.