{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,10]],"date-time":"2026-02-10T08:28:30Z","timestamp":1770712110197,"version":"3.49.0"},"reference-count":40,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T00:00:00Z","timestamp":1717977600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Foundation for Science and Technology (FCT)","award":["UIDB\/50026\/2020"],"award-info":[{"award-number":["UIDB\/50026\/2020"]}]},{"name":"Foundation for Science and Technology (FCT)","award":["UIDP\/50026\/2020"],"award-info":[{"award-number":["UIDP\/50026\/2020"]}]},{"name":"Foundation for Science and Technology (FCT)","award":["LA\/P\/0050\/2020"],"award-info":[{"award-number":["LA\/P\/0050\/2020"]}]},{"name":"Foundation for Science and Technology (FCT)","award":["SFRH\/BD\/141200\/2018"],"award-info":[{"award-number":["SFRH\/BD\/141200\/2018"]}]},{"name":"Foundation for Science and Technology (FCT)","award":["2021.08171.BD"],"award-info":[{"award-number":["2021.08171.BD"]}]},{"name":"Foundation for Science and Technology (FCT)","award":["2021.07647.BD"],"award-info":[{"award-number":["2021.07647.BD"]}]},{"name":"Foundation for Science and Technology (FCT)","award":["SFRH\/BD\/148199\/2019"],"award-info":[{"award-number":["SFRH\/BD\/148199\/2019"]}]},{"name":"Foundation for Science and Technology (FCT)","award":["PD\/BDE\/150611\/2020"],"award-info":[{"award-number":["PD\/BDE\/150611\/2020"]}]},{"name":"Foundation for Science and Technology (FCT)","award":["NORTE-01-0145-FEDER-000055"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000055"]}]},{"name":"Foundation for Science and Technology (FCT)","award":["NORTE-01-0247-FEDER-04914"],"award-info":[{"award-number":["NORTE-01-0247-FEDER-04914"]}]},{"name":"European Regional Development Fund (ERDF)","award":["UIDB\/50026\/2020"],"award-info":[{"award-number":["UIDB\/50026\/2020"]}]},{"name":"European Regional Development Fund (ERDF)","award":["UIDP\/50026\/2020"],"award-info":[{"award-number":["UIDP\/50026\/2020"]}]},{"name":"European Regional Development Fund (ERDF)","award":["LA\/P\/0050\/2020"],"award-info":[{"award-number":["LA\/P\/0050\/2020"]}]},{"name":"European Regional Development Fund (ERDF)","award":["SFRH\/BD\/141200\/2018"],"award-info":[{"award-number":["SFRH\/BD\/141200\/2018"]}]},{"name":"European Regional Development Fund (ERDF)","award":["2021.08171.BD"],"award-info":[{"award-number":["2021.08171.BD"]}]},{"name":"European Regional Development Fund (ERDF)","award":["2021.07647.BD"],"award-info":[{"award-number":["2021.07647.BD"]}]},{"name":"European Regional Development Fund (ERDF)","award":["SFRH\/BD\/148199\/2019"],"award-info":[{"award-number":["SFRH\/BD\/148199\/2019"]}]},{"name":"European Regional Development Fund (ERDF)","award":["PD\/BDE\/150611\/2020"],"award-info":[{"award-number":["PD\/BDE\/150611\/2020"]}]},{"name":"European Regional Development Fund (ERDF)","award":["NORTE-01-0145-FEDER-000055"],"award-info":[{"award-number":["NORTE-01-0145-FEDER-000055"]}]},{"name":"European Regional Development Fund (ERDF)","award":["NORTE-01-0247-FEDER-04914"],"award-info":[{"award-number":["NORTE-01-0247-FEDER-04914"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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.<\/jats:p>","DOI":"10.3390\/cancers16122182","type":"journal-article","created":{"date-parts":[[2024,6,10]],"date-time":"2024-06-10T08:59:06Z","timestamp":1718009946000},"page":"2182","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Unveiling the RKIP and EGFR Inverse Relationship in Solid Tumors: A Case Study in Cervical Cancer"],"prefix":"10.3390","volume":"16","author":[{"given":"Diana","family":"Cardoso-Carneiro","sequence":"first","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}]},{"given":"Joana","family":"Pinheiro","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-0562-3148","authenticated-orcid":false,"given":"Patr\u00edcia","family":"Font\u00e3o","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}]},{"given":"Rosete","family":"Nogueira","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"},{"name":"CGC Genetics\/Centro de Gen\u00e9tica Cl\u00ednica, Unilabs-Laboratory of Pathology, 4000-432 Porto, Portugal"}]},{"given":"Maria","family":"Gabriela-Freitas","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9760-7605","authenticated-orcid":false,"given":"Ana","family":"Raquel-Cunha","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7606-1780","authenticated-orcid":false,"given":"Adriana","family":"Mendes","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5779-9752","authenticated-orcid":false,"given":"Adhemar","family":"Longatto-Filho","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"},{"name":"Medical Laboratory of Medical Investigation (LIM), Department of Pathology, Medical School, University of S\u00e3o Paulo, S\u00e3o Paulo 01246-903, SP, Brazil"},{"name":"Molecular Oncology Research Center (CPOM), Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil"}]},{"given":"F\u00e1bio","family":"Marques","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Federal University of Goi\u00e1s, Goi\u00e1s 74605-050, GO, Brazil"}]},{"given":"Marise A. R.","family":"Moreira","sequence":"additional","affiliation":[{"name":"Department of Pathology, School of Medicine, Federal University of Goi\u00e1s, Goi\u00e1s 74605-050, GO, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9639-7940","authenticated-orcid":false,"given":"Rui M.","family":"Reis","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"},{"name":"Molecular Oncology Research Center (CPOM), Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3221-0403","authenticated-orcid":false,"given":"Olga","family":"Martinho","sequence":"additional","affiliation":[{"name":"Life and Health Sciences Research Institute (ICVS), Health Sciences School, University of Minho, 4710-057 Braga, Portugal"},{"name":"ICVS\/3B\u2019s\u2014PT Government Associate Laboratory, 4710-057 Braga, Portugal"},{"name":"Molecular Oncology Research Center (CPOM), Barretos Cancer Hospital, Barretos 14784-400, SP, Brazil"}]}],"member":"1968","published-online":{"date-parts":[[2024,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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