Abstract

Human papillomaviruses (HPVs) cause virtually all cervical cancer cases and are also associated with other types of anogenital and oropharyngeal cancers. HPV-mediated carcinogenesis typically begins with the HPV episome integrating into the human genome. Unfortunately, the factors that promote this key process are not well defined. Since viral integration requires breaks in both viral and human genomes, DNA damage is likely a key determinant. The latter is primarily caused by an overproduction of reactive oxygen species (ROS). Therefore, high levels of background ROS in host cells, which may result from genetic/epigenetic factors together with exogenous influences, in principle, have the potential to promote carcinogenesis in HPV-infected individuals. To ask whether such variability indeed existed, we assessed ROS and 8-oxoG levels in non-cancerous cervical samples and showed remarkable variability between different patient specimens. These findings suggest that the susceptibility of HPV-infected individuals to develop cervical cancer may be different due to variability in ROS levels and probability of HPV integration. Another potentially significant source of DNA damage is exposure to elevated doses of ionizing radiation. Natural background radiation is ubiquitous; however, some populations, including radiological workers, radiotherapy patients, and astronauts are exposed to significantly higher radiation doses. We therefore examined the impact of ionizing radiation exposure on DNA damage and integration frequency, and we demonstrated that ionizing radiation exposure induces both direct and indirect (ROS-induced) DNA damage in oral and cervical keratinocytes and promotes the integration of foreign circular plasmid into the human genome. These findings propose that radiation-induced DNA damage puts the exposed population at higher risk of developing HPV-related cancers. Overall, the insights gained from this work enable us to better understand the contribution of oxidative stress and radiation exposure to HPV-mediated carcinogenesis and direct us toward strategies aimed at preventing malignancies in HPV-infected individuals.

LLU Discipline

Biochemistry

Department

Biochemistry

School

School of Medicine

First Advisor

Penelope J. Duerksen-Hughes

Second Advisor

Carlos Casiano

Third Advisor

Ubaldo Soto

Fourth Advisor

Juli Unternaehrer

Fifth Advisor

Xin Sean Chen

Sixth Advisor

Valery Filippov

Degree Name

Doctor of Philosophy (PhD)

Degree Level

Ph.D.

Year Degree Awarded

2021

Date (Title Page)

4-2021

Language

English

Library of Congress/MESH Subject Headings

Human Papillomavirus Infections; DNA Damage; Oxidative Stress; Carcinogenesis; Viral Integration

Type

Dissertation

Page Count

xix, 181 p.

Digital Format

PDF

Digital Publisher

Loma Linda University Libraries

Usage Rights

This title appears here courtesy of the author, who has granted Loma Linda University a limited, non-exclusive right to make this publication available to the public. The author retains all other copyrights.

Collection

Loma Linda University Electronic Theses and Dissertations

Collection Website

http://scholarsrepository.llu.edu/etd/

Repository

Loma Linda University. Del E. Webb Memorial Library. University Archives

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