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

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2020Author
Mendaza, Saioa
Fernández-Irigoyen, Joaquín
Santamaría, Enrique
Zudaire, Tamara
Guarch, Rosa
Guerrero-Setas, David
Vidal, August
Santos-Salas, José
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.
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Show full item recordAbstract
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.
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International Journal of Molecular Sciences, 2020, vol. 21, núm. 6, p. 2125European research projects
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