Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix
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 expr...
| Autores: | , , , , , |
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| Tipo de recurso: | artículo |
| Estado: | Versión publicada |
| Fecha de publicación: | 2020 |
| País: | España |
| Institución: | Universidad Pública de Navarra |
| Repositorio: | Academica-e. Repositorio Institucional de la Universidad Pública de Navarra |
| OAI Identifier: | oai:academica-e.unavarra.es:2454/37755 |
| Acceso en línea: | https://hdl.handle.net/2454/37755 |
| Access Level: | acceso abierto |
| Palabra clave: | Cytoplasmic p16 Nuclear p16 Subcellular location Predictive biomarker Squamous cell carcinoma of the cervix High-grade squamous intraepithelial lesion Cervical cancer |
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Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervixMendaza Lainez, SaioaFernández Irigoyen, JoaquínSantamaría Martínez, EnriqueZudaire, TamaraGuarch, RosaGuerrero Setas, DavidCytoplasmic p16Nuclear p16Subcellular locationPredictive biomarkerSquamous cell carcinoma of the cervixHigh-grade squamous intraepithelial lesionCervical cancerThe 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.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).MDPICiencias de la SaludOsasun ZientziakGobierno de Navarra / Nafarroako GobernuaUniversidad Pública de Navarra / Nafarroako Unibertsitate Publikoa2020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/ziphttps://hdl.handle.net/2454/37755reponame:Academica-e. Repositorio Institucional de la Universidad Pública de Navarrainstname:Universidad Pública de NavarraInglés© 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.https://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:academica-e.unavarra.es:2454/377552026-06-17T12:41:47Z |
| dc.title.none.fl_str_mv |
Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix |
| title |
Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix |
| spellingShingle |
Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix Mendaza Lainez, Saioa Cytoplasmic p16 Nuclear p16 Subcellular location Predictive biomarker Squamous cell carcinoma of the cervix High-grade squamous intraepithelial lesion Cervical cancer |
| title_short |
Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix |
| title_full |
Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix |
| title_fullStr |
Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix |
| title_full_unstemmed |
Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix |
| title_sort |
Absence of nuclear p16 is a diagnostic and independent prognostic biomarker in squamous cell carcinoma of the cervix |
| dc.creator.none.fl_str_mv |
Mendaza Lainez, Saioa Fernández Irigoyen, Joaquín Santamaría Martínez, Enrique Zudaire, Tamara Guarch, Rosa Guerrero Setas, David |
| author |
Mendaza Lainez, Saioa |
| author_facet |
Mendaza Lainez, Saioa Fernández Irigoyen, Joaquín Santamaría Martínez, Enrique Zudaire, Tamara Guarch, Rosa Guerrero Setas, David |
| author_role |
author |
| author2 |
Fernández Irigoyen, Joaquín Santamaría Martínez, Enrique Zudaire, Tamara Guarch, Rosa Guerrero Setas, David |
| author2_role |
author author author author author |
| dc.contributor.none.fl_str_mv |
Ciencias de la Salud Osasun Zientziak Gobierno de Navarra / Nafarroako Gobernua Universidad Pública de Navarra / Nafarroako Unibertsitate Publikoa |
| dc.subject.none.fl_str_mv |
Cytoplasmic p16 Nuclear p16 Subcellular location Predictive biomarker Squamous cell carcinoma of the cervix High-grade squamous intraepithelial lesion Cervical cancer |
| topic |
Cytoplasmic p16 Nuclear p16 Subcellular location Predictive biomarker Squamous cell carcinoma of the cervix High-grade squamous intraepithelial lesion Cervical cancer |
| description |
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. |
| publishDate |
2020 |
| dc.date.none.fl_str_mv |
2020 |
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info:eu-repo/semantics/article info:eu-repo/semantics/publishedVersion |
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article |
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publishedVersion |
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https://hdl.handle.net/2454/37755 |
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https://hdl.handle.net/2454/37755 |
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Inglés |
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Inglés |
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https://creativecommons.org/licenses/by/4.0/ info:eu-repo/semantics/openAccess |
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https://creativecommons.org/licenses/by/4.0/ |
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openAccess |
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MDPI |
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MDPI |
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