Absence of Nuclear p16 Is a Diagnostic and Independent Prognostic Biomarker in Squamous Cell Carcinoma of the Cervix

Mendaza, Saioa; Fernández-Irigoyen, Joaquín; Santamaría, Enrique; Zudaire, Tamara; Guarch, Rosa; Guerrero-Setas, David; Vidal, August; Santos-Salas, José; Matias-Guiu, Xavier; Ausín, Karina; Díaz de Cerio, María José; Martín-Sánchez, Esperanza

doi:https://doi.org/10.3390/ijms21062125

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Issue date

2020

Author

Mendaza, Saioa

Fernández-Irigoyen, Joaquín

Santamaría, Enrique

Zudaire, Tamara

Guarch, Rosa

Guerrero-Setas, David

Vidal, August

Santos-Salas, José

Matias-Guiu, Xavier

Ausín, Karina

Díaz de Cerio, María José

Martín-Sánchez, Esperanza

Suggested citation

Mendaza, Saioa; Fernández-Irigoyen, Joaquín; Santamaría, Enrique; Zudaire, Tamara; Guarch, Rosa; Guerrero-Setas, David; ... Martín-Sánchez, Esperanza. (2020) . Absence of Nuclear p16 Is a Diagnostic and Independent Prognostic Biomarker in Squamous Cell Carcinoma of the Cervix. International Journal of Molecular Sciences, 2020, vol. 21, núm. 6, p. 2125. https://doi.org/10.3390/ijms21062125.

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.

URI

http://hdl.handle.net/10459.1/70764

DOI

https://doi.org/10.3390/ijms21062125

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International Journal of Molecular Sciences, 2020, vol. 21, núm. 6, p. 2125

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Except where otherwise noted, this item's license is described as cc-by, (c) Mendaza et al., 2020