Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix

Mendaza Lainez, Saioa; Fernández Irigoyen, Joaquín; Santamaría Martínez, Enrique; Zudaire, Tamara; Guarch, Rosa; Guerrero Setas, David

Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix

dc.contributor.author	Mendaza Lainez, Saioa
dc.contributor.author	Fernández Irigoyen, Joaquín
dc.contributor.author	Santamaría Martínez, Enrique
dc.contributor.author	Zudaire, Tamara
dc.contributor.author	Guarch, Rosa
dc.contributor.author	Guerrero Setas, David
dc.contributor.department	Ciencias de la Salud	es_ES
dc.contributor.department	Osasun Zientziak	eu
dc.contributor.funder	Gobierno de Navarra / Nafarroako Gobernua	es
dc.contributor.funder	Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa	es
dc.date.accessioned	2020-08-06T08:35:34Z
dc.date.available	2020-08-06T08:35:34Z
dc.date.issued	2020
dc.description.abstract	The tumor-suppressor protein p16 is paradoxically overexpressed in cervical cancer (CC). Despite its potential as a biomarker, its clinical value and the reasons for its failure in tumor suppression remain unclear. Our purpose was to determine p16 clinical and biological significance in CC. p16 expression pattern was examined by immunohistochemistry in 78 CC cases (high-grade squamous intraepithelial lesions (HSILs) and squamous cell carcinomas of the cervix –SCCCs). CC cell proliferation and invasion were monitored by real-time cell analysis and Transwell® invasion assay, respectively. Cytoplasmic p16 interactors were identified from immunoprecipitated extracts by liquid chromatography-tandem mass spectrometry, and colocalization was confirmed by double-immunofluorescence. We observed that SCCCs showed significantly more cytoplasmic than nuclear p16 expression than HSILs. Importantly, nuclear p16 absence significantly predicted poor outcome in SCCC patients irrespective of other clinical parameters. Moreover, we demonstrated that cytoplasmic p16 interacted with CDK4 and other unreported proteins, such as BANF1, AKAP8 and AGTRAP, which could sequester p16 to avoid nuclear translocation, and then, impair its anti-tumor function. Our results suggest that the absence of nuclear p16 could be a diagnostic biomarker between HSIL and SCCC, and an independent prognostic biomarker in SCCC; and explain why p16 overexpression fails to stop CC growth.	en
dc.description.sponsorship	This research was funded by the Health Department of the Navarre Government (Grant number 21/11), the Navarre Breast Cancer Patients’ Association (SARAY) and the 'Proof of concept project on proteomic research' from Proteored (Grant number ProteoRed-0000029). The Proteomics Unit of Navarrabiomed is a member of Proteored, PRB3-ISCIII, and is supported by Grant PT17/0019/009, of the PE I + D + I 2013–2016 funded by ISCIII and ERDF. S.M. was a recipient of a predoctoral grant from the Public University of Navarre. E.M.-S. was a recipient of a fellowship from the Spanish Ministry of Science, Innovation and Universities (PTA2015-11895-I).	en
dc.format.extent	16 p.
dc.format.mimetype	application/pdf	en
dc.format.mimetype	application/zip	en
dc.identifier.doi	10.3390/ijms21062125
dc.identifier.issn	1661-6596
dc.identifier.uri	https://academica-e.unavarra.es/handle/2454/37755
dc.language.iso	eng	en
dc.publisher	MDPI	en
dc.relation.ispartof	International Journal of Molecular Sciences, 2020, 21 (6), 2125	en
dc.relation.publisherversion	https://doi.org/10.3390/ijms21062125
dc.rights	© 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license.	en
dc.rights.accessRights	info:eu-repo/semantics/openAccess
dc.rights.uri	https://creativecommons.org/licenses/by/4.0/
dc.subject	Cytoplasmic p16	en
dc.subject	Nuclear p16	en
dc.subject	Subcellular location	en
dc.subject	Predictive biomarker	en
dc.subject	Squamous cell carcinoma of the cervix	en
dc.subject	High-grade squamous intraepithelial lesion	en
dc.subject	Cervical cancer	en
dc.title	Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix	en
dc.type	info:eu-repo/semantics/article
dc.type.version	info:eu-repo/semantics/publishedVersion
dspace.entity.type	Publication
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