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- Title
Unveiling the RKIP and EGFR Inverse Relationship in Solid Tumors: A Case Study in Cervical Cancer.
- Authors
Cardoso-Carneiro, Diana; Pinheiro, Joana; Fontão, Patrícia; Nogueira, Rosete; Gabriela-Freitas, Maria; Raquel-Cunha, Ana; Mendes, Adriana; Longatto-Filho, Adhemar; Marques, Fábio; Moreira, Marise A. R.; Reis, Rui M.; Martinho, Olga
- Abstract
Simple Summary: For the first time, we hypothesized an inverse correlation and almost mutual exclusivity between RKIP and EGFR expression in different solid tumors. In silico, cervical cancer was the third tumor type in which this inverse correlation was strong, a result that we validated in a series of 202 patient samples. Importantly, we highlight the importance of this axis by demonstrating its strong association with patient prognosis. Using in vitro functional assays, we showed that RKIP can control EGFR mRNA expression as well as its phosphorylation status, while EGFR activation can also interfere with RKIP protein expression levels. Therefore, the discovery of this novel putative RKIP/EGFR loop opens the door for several interesting future studies in many other tumor types, mainly those in which EGFR has a crucial oncogenic role. 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.
- Subjects
IN vitro studies; CERVIX uteri tumors; CARRIER proteins; PHOSPHORYLATION; RESEARCH funding; CELLULAR signal transduction; DESCRIPTIVE statistics; LONGITUDINAL method; MESSENGER RNA; CELL lines; GENE expression profiling; ONCOGENES; EPIDERMAL growth factor receptors; DISEASE progression
- Publication
Cancers, 2024, Vol 16, Issue 12, p2182
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers16122182