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

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....

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Autores principales: Mittal, Karuna, Choi, Da Hoon, Wei, Guanhao, Kaur, Jaspreet, Klimov, Sergey, Arora, Komal, Griffith, Christopher C., Kumar, Mukesh, Imhansi-Jacob, Precious, Melton, Brian D., Bhimji-Pattni, Sonal, Osan, Remus M., Rida, Padmashree, Golusinski, Paweł, Aneja, Ritu
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072660/
https://www.ncbi.nlm.nih.gov/pubmed/32102296
http://dx.doi.org/10.3390/cancers12020517
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author Mittal, Karuna
Choi, Da Hoon
Wei, Guanhao
Kaur, Jaspreet
Klimov, Sergey
Arora, Komal
Griffith, Christopher C.
Kumar, Mukesh
Imhansi-Jacob, Precious
Melton, Brian D.
Bhimji-Pattni, Sonal
Osan, Remus M.
Rida, Padmashree
Golusinski, Paweł
Aneja, Ritu
author_facet Mittal, Karuna
Choi, Da Hoon
Wei, Guanhao
Kaur, Jaspreet
Klimov, Sergey
Arora, Komal
Griffith, Christopher C.
Kumar, Mukesh
Imhansi-Jacob, Precious
Melton, Brian D.
Bhimji-Pattni, Sonal
Osan, Remus M.
Rida, Padmashree
Golusinski, Paweł
Aneja, Ritu
author_sort Mittal, Karuna
collection PubMed
description 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.
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spelling pubmed-70726602020-03-19 Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas Mittal, Karuna Choi, Da Hoon Wei, Guanhao Kaur, Jaspreet Klimov, Sergey Arora, Komal Griffith, Christopher C. Kumar, Mukesh Imhansi-Jacob, Precious Melton, Brian D. Bhimji-Pattni, Sonal Osan, Remus M. Rida, Padmashree Golusinski, Paweł Aneja, Ritu Cancers (Basel) Article 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. MDPI 2020-02-24 /pmc/articles/PMC7072660/ /pubmed/32102296 http://dx.doi.org/10.3390/cancers12020517 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mittal, Karuna
Choi, Da Hoon
Wei, Guanhao
Kaur, Jaspreet
Klimov, Sergey
Arora, Komal
Griffith, Christopher C.
Kumar, Mukesh
Imhansi-Jacob, Precious
Melton, Brian D.
Bhimji-Pattni, Sonal
Osan, Remus M.
Rida, Padmashree
Golusinski, Paweł
Aneja, Ritu
Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas
title Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas
title_full Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas
title_fullStr Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas
title_full_unstemmed Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas
title_short Hypoxia-Induced Centrosome Amplification Underlies Aggressive Disease Course in HPV-Negative Oropharyngeal Squamous Cell Carcinomas
title_sort hypoxia-induced centrosome amplification underlies aggressive disease course in hpv-negative oropharyngeal squamous cell carcinomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072660/
https://www.ncbi.nlm.nih.gov/pubmed/32102296
http://dx.doi.org/10.3390/cancers12020517
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