Abstract
Human papillomavirus-negative (HPV-neg) oropharyngeal squamous cell carcinomas (OPSCCs) are associated with poorer overall survival (OS) compared with HPV-positive (HPV-pos) OPSCCs. The major obstacle in improving outcomes of HPV-neg patients is the lack of robust biomarkers and therapeutic targets. Herein, we investigated the role of centrosome amplification (CA) as a prognostic biomarker in HPV-neg OPSCCs. A quantitative evaluation of CA in clinical specimens of OPSCC revealed that (a) HPV-neg OPSCCs exhibit higher CA compared with HPV-pos OPSCCs, and (b) CA was associated with poor OS, even after adjusting for potentially confounding clinicopathologic variables. Contrastingly, CA was higher in HPV-pos cultured cell lines compared to HPV-neg ones. This divergence in CA phenotypes between clinical specimens and cultured cells can therefore be attributed to an inaccurate recapitulation of the in vivo tumor microenvironment in the cultured cell lines, namely a hypoxic environment. The exposure of HPV-neg OPSCC cultured cells to hypoxia or stabilizing HIF-1α genetically increased CA. Both the 26-gene hypoxia signature as well as the overexpression of HIF-1α positively correlated with increased CA in HPV-neg OPSCCs. In addition, we showed that HIF-1α upregulation is associated with the downregulation of miR-34a, increase in CA and expression of cyclin- D1. Our findings demonstrate that the evaluation of CA may aid in therapeutic decision-making, and CA can serve as a promising therapeutic target for HPV-neg OPSCC patients.
Highlights
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide [1]. the incidence and mortality rates for HNSCC are declining globally, there has been a gradual increase in the incidence rate of oropharyngeal squamous cell carcinomas (OPSCCs) in recent years [2].OPSCC is a type of HNSCC, which includes cancer of the tonsils, base of the tongue, back of the roof of the mouth and the side and back walls of the throat
Given that the human papillomavirus (HPV)-neg OPSCCs exhibit a higher expression of DNA damage response genes and are associated with a more aggressive disease course and poorer overall survival than HPV-pos OPSCCs, we postulated that HPV-neg tumors might exhibit significant centrosome amplification (CA)
In the analysis of the subset consisting of only OPSCCs among the cohort, we found similar results, wherein
Summary
Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide [1]. the incidence and mortality rates for HNSCC are declining globally, there has been a gradual increase in the incidence rate of oropharyngeal squamous cell carcinomas (OPSCCs) in recent years [2].OPSCC is a type of HNSCC, which includes cancer of the tonsils, base of the tongue, back of the roof of the mouth and the side and back walls of the throat. Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide [1]. The incidence and mortality rates for HNSCC are declining globally, there has been a gradual increase in the incidence rate of oropharyngeal squamous cell carcinomas (OPSCCs) in recent years [2]. A major factor underlying the increased incidence rate of OPSCCs is human papillomavirus (HPV) infection [3]. A randomized trial comparing accelerated-fractionation with standard-fractionation radiotherapy, in combination with cisplatin therapy showed better rates of three-year overall survival (82.4%) in HPV-pos OPSCC patients compared to their HPV-neg counterparts (57.1%) [4]. In the absence of a good therapeutic target, conventional chemotherapy is still the mainstay of treatment for HPV-neg OPSCC patients, whose prognosis remains dismal
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