Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins

ABSTRACT The E6 and E7 proteins are the major oncogenic drivers encoded by high-risk human papillomaviruses (HPVs). While many aspects of the transforming activities of these proteins have been extensively studied, there are fewer studies that have investigated how HPV E6/E7 expression affects the e...

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Autores principales:	Mallory E. Harden, Nripesh Prasad, Anthony Griffiths, Karl Munger
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2017
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/23efd2b9adb642f686a404f5d620ffbc
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spelling	oai:doaj.org-article:23efd2b9adb642f686a404f5d620ffbc2021-11-15T15:51:06ZModulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins10.1128/mBio.02170-162150-7511https://doaj.org/article/23efd2b9adb642f686a404f5d620ffbc2017-03-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.02170-16https://doaj.org/toc/2150-7511ABSTRACT The E6 and E7 proteins are the major oncogenic drivers encoded by high-risk human papillomaviruses (HPVs). While many aspects of the transforming activities of these proteins have been extensively studied, there are fewer studies that have investigated how HPV E6/E7 expression affects the expression of cellular noncoding RNAs. The goal of our study was to investigate HPV16 E6/E7 modulation of cellular microRNA (miR) levels and to determine the potential consequences for cellular gene expression. We performed deep sequencing of small and large cellular RNAs in primary undifferentiated cultures of human foreskin keratinocytes (HFKs) with stable expression of HPV16 E6/E7 or a control vector. After integration of the two data sets, we identified 51 differentially expressed cellular miRs associated with the modulation of 1,456 potential target mRNAs in HPV16 E6/E7-expressing HFKs. We discovered that the degree of differential miR expression in HFKs expressing HPV16 E6/E7 was not necessarily predictive of the number of corresponding mRNA targets or the potential impact on gene expression. Additional analyses of the identified miR-mRNA pairs suggest modulation of specific biological activities and biochemical pathways. Overall, our study supports the model that perturbation of cellular miR expression by HPV16 E6/E7 importantly contributes to the rewiring of cellular regulatory circuits by the high-risk HPV E6 and E7 proteins that contribute to oncogenic transformation. IMPORTANCE High-risk human papillomaviruses (HPVs) are the causative agents of almost all cervical cancers and many other cancers, including anal, vaginal, vulvar, penile, and oropharyngeal cancers. Despite the availability of efficacious HPV vaccines, it is critical to determine how HPVs cause cancer, as many people remain unvaccinated and the vaccine does not prevent cancer development in individuals who are already infected. Two HPV proteins, E6 and E7, are the major drivers of cancer development, and much remains to be learned about how the expression of these viral proteins reprograms infected cells, ultimately resulting in cancer development. Small, noncoding human RNAs, termed microRNAs (miRs), regulate gene expression and have been implicated in almost all human cancers, including HPV-associated cancers. Our study provides a comprehensive analysis of how E6 and E7 alter the expression of human miRs and how this potentially impacts cellular gene expression, which may contribute to cancer development.Mallory E. HardenNripesh PrasadAnthony GriffithsKarl MungerAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 8, Iss 1 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 Mallory E. Harden Nripesh Prasad Anthony Griffiths Karl Munger Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins
description	ABSTRACT The E6 and E7 proteins are the major oncogenic drivers encoded by high-risk human papillomaviruses (HPVs). While many aspects of the transforming activities of these proteins have been extensively studied, there are fewer studies that have investigated how HPV E6/E7 expression affects the expression of cellular noncoding RNAs. The goal of our study was to investigate HPV16 E6/E7 modulation of cellular microRNA (miR) levels and to determine the potential consequences for cellular gene expression. We performed deep sequencing of small and large cellular RNAs in primary undifferentiated cultures of human foreskin keratinocytes (HFKs) with stable expression of HPV16 E6/E7 or a control vector. After integration of the two data sets, we identified 51 differentially expressed cellular miRs associated with the modulation of 1,456 potential target mRNAs in HPV16 E6/E7-expressing HFKs. We discovered that the degree of differential miR expression in HFKs expressing HPV16 E6/E7 was not necessarily predictive of the number of corresponding mRNA targets or the potential impact on gene expression. Additional analyses of the identified miR-mRNA pairs suggest modulation of specific biological activities and biochemical pathways. Overall, our study supports the model that perturbation of cellular miR expression by HPV16 E6/E7 importantly contributes to the rewiring of cellular regulatory circuits by the high-risk HPV E6 and E7 proteins that contribute to oncogenic transformation. IMPORTANCE High-risk human papillomaviruses (HPVs) are the causative agents of almost all cervical cancers and many other cancers, including anal, vaginal, vulvar, penile, and oropharyngeal cancers. Despite the availability of efficacious HPV vaccines, it is critical to determine how HPVs cause cancer, as many people remain unvaccinated and the vaccine does not prevent cancer development in individuals who are already infected. Two HPV proteins, E6 and E7, are the major drivers of cancer development, and much remains to be learned about how the expression of these viral proteins reprograms infected cells, ultimately resulting in cancer development. Small, noncoding human RNAs, termed microRNAs (miRs), regulate gene expression and have been implicated in almost all human cancers, including HPV-associated cancers. Our study provides a comprehensive analysis of how E6 and E7 alter the expression of human miRs and how this potentially impacts cellular gene expression, which may contribute to cancer development.
format	article
author	Mallory E. Harden Nripesh Prasad Anthony Griffiths Karl Munger
author_facet	Mallory E. Harden Nripesh Prasad Anthony Griffiths Karl Munger
author_sort	Mallory E. Harden
title	Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins
title_short	Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins
title_full	Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins
title_fullStr	Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins
title_full_unstemmed	Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins
title_sort	modulation of microrna-mrna target pairs by human papillomavirus 16 oncoproteins
publisher	American Society for Microbiology
publishDate	2017
url	https://doaj.org/article/23efd2b9adb642f686a404f5d620ffbc
work_keys_str_mv	AT malloryeharden modulationofmicrornamrnatargetpairsbyhumanpapillomavirus16oncoproteins AT nripeshprasad modulationofmicrornamrnatargetpairsbyhumanpapillomavirus16oncoproteins AT anthonygriffiths modulationofmicrornamrnatargetpairsbyhumanpapillomavirus16oncoproteins AT karlmunger modulationofmicrornamrnatargetpairsbyhumanpapillomavirus16oncoproteins
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Modulation of microRNA-mRNA Target Pairs by Human Papillomavirus 16 Oncoproteins

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