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.
Highlights
Squamous cell carcinoma of the cervix (SCCC) accounts for 70–80% of all cervical cancer (CC) cases, which is the fourth most frequent cancer type in women worldwide [1], with a 5-year survival of 57–67% in Europe [2]
As there is a lack of consensus and clear guidelines regarding the use of p16 expression in routine clinical management of SCCC [2,5,19], we aimed to shed some light on the clinical utility and biological significance of p16 overexpression during SCCC progression
Global p16 expression was examined in our series of 29 high-grade squamous intraepithelial lesion (HSIL) and 49 SCCCs, taking into account the criteria which are routinely used in the clinical practice
Summary
Squamous cell carcinoma of the cervix (SCCC) accounts for 70–80% of all cervical cancer (CC) cases, which is the fourth most frequent cancer type in women worldwide [1], with a 5-year survival of 57–67% in Europe [2]. SCCC pathogenesis is a slow multi-stage process: when a high-risk human papillomavirus (HR-HPV) infection—present in 99.7% of cases [2,3]—persists in dividing cells, these can originate a high-grade squamous intraepithelial lesion (HSIL); if, some molecular alterations occur, tumor cells extend beyond the basement membrane of the epithelium, and an invasive carcinoma appears [3,4]. As CC development seems to be a continuous process, it is quite difficult to morphologically distinguish an HSIL which has begun to invade and an SCCC which has just penetrated the basement membrane. These apparently similar tumors display very different clinical behaviors. An accurate diagnosis is crucial for the successful clinical management of these patients
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