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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....
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
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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. |
format | Online Article Text |
id | pubmed-7072660 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
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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