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.
Raf激酶抑制蛋白（RKIP）被确认为一种真正的肿瘤抑制基因，其表达减少或缺失与多种实体肿瘤的进展及不良预后相关。该蛋白通过调控包括MAPK等HER受体介导的多种细胞内信号通路，在肿瘤发生过程中发挥多层面作用。鉴于HER受体过表达在多种肿瘤类型中的重要意义，本研究探讨了实体肿瘤中RKIP与HER受体之间潜在的致癌关联。通过对涵盖实体肿瘤的30项TCGA泛癌图谱研究（共10,719例样本）进行全面的生物信息学分析，我们在30项研究中的25项中发现了RKIP与EGFR表达呈负相关的有力证据。相反，其他HER受体（ERBB2、ERBB3和ERBB4）则主要呈现正相关。特别值得注意的是，宫颈癌（CC）作为肿瘤类型之一，表现出RKIP与EGFR表达之间强烈的负相关，这一发现在202例患者样本队列中得到了进一步验证。后续通过药理学和遗传学方法调控EGFR和RKIP的体外实验表明：RKIP耗竭会导致EGFR mRNA水平显著上调并诱导EGFR磷酸化；反之，EGFR过度激活则会降低CC细胞系中RKIP的表达。此外，我们发现了低RKIP与高EGFR表达患者共有的分子特征，并证实了这种负相关在宫颈癌患者中的预后价值。综上所述，我们的研究揭示了多种实体肿瘤中RKIP与EGFR表达呈负相关，为理解宫颈癌中RKIP与EGFR相关侵袭性表型的潜在分子机制提供了新的视角。
Unveiling the RKIP and EGFR Inverse Relationship in Solid Tumors: A Case Study in Cervical Cancer
肿瘤(癌症)患者之家