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Open AccessArticle

Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas

1
Department of Biology, Georgia State University, Atlanta, GA 30303, USA
2
Emory Hospital Midtown, Atlanta, GA 30308, USA
3
Novazoi Theranostics, Rancho Palos Verdes, CA 90725, USA
4
Department of Otolaryngology and Maxillofacial Surgery, University of Zielona Gora, 65-417 Zielona Gora, Poland
5
Department of Biology and Environmental Sciences, Poznan University of Medical Sciences, 61-701 Poznan, Poland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Cancers 2020, 12(2), 517; https://doi.org/10.3390/cancers12020517
Received: 11 December 2019 / Revised: 7 February 2020 / Accepted: 17 February 2020 / Published: 24 February 2020
(This article belongs to the Special Issue Human Papillomavirus and Cancers)
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. View Full-Text
Keywords: hypoxia; human papillomavirus; oropharyngeal squamous cell carcinoma; centrosome amplification; miRNA hypoxia; human papillomavirus; oropharyngeal squamous cell carcinoma; centrosome amplification; miRNA
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Mittal, K.; Choi, D.H.; Wei, G.; Kaur, J.; Klimov, S.; Arora, K.; Griffith, C.C.; Kumar, M.; Imhansi-Jacob, P.; Melton, B.D.; Bhimji-Pattni, S.; Osan, R.M.; Rida, P.; Golusinski, P.; Aneja, R. Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas. Cancers 2020, 12, 517.

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