Date of Award

2015

Document Type

Open Access Thesis

Department

Biological Sciences

First Advisor

Lucia Pirisi-Creek

Abstract

Head and Neck Squamous Carcinoma (HNSCC) is one of the most common cancers worldwide. HNSCC affects regions of the upper aerodigestive tract such as the lip, tongue, nasopharynx, oropharynx, larynx, and hypopharynx. About 25% of all HNSCC cases and up to 65% of Oropharyngeal Carcinoma (OPC) cases are positive for HPV DNA. African American patients, especially males, present primarily with HPV-negative HNSCC. HNSCC’s that are HPV-positive tend to be HPV-active at initial presentation: these cancers contain HPV DNA and express HPV RNA. However, recurring HPV-positive cancers of the head and neck are more often inactive: these tumors contain HPV DNA, but do not express viral mRNA. Previous gene expression profiling results identify a gene expression signature of HPV-inactive tumors that is “intermediate” between HPV-active and HPV-negative cancers. This study focuses on the molecular characteristics of HPV-inactive tumors and the molecular mechanisms by which these tumors may lose E6 and E7 oncogene expression. E6 and E7 are viral oncogenes whose expression drives cells to proliferate indefinitely and lose sensitivity to senescence and growth arrest mechanisms (immortalization). Our hypothesis is that tumors that are HPV-inactive began as HPV-active lesions, where tumor cells lost expression of E6/E7 by either mutation or epigenetic mechanisms or both. In these tumors, the growth promoting effects of E6/E7 should be replaced by mutations of relevant key genes. This project is aimed towards uncovering specific molecular mechanisms by which HPV-transformed cells can escape the need for continuous E6/E7 expression for proliferation. In order to explore our hypothesis, we have developed two specific aims: 1) to determine whether mutated H-Ras (H-RasV12) expression results in changes in E7 mRNA and Rb protein levels in HKc. Our results indicate that H-RasV12 partially replaces E7 function. 2) To determine whether p53 knock-down by the means of an shRNA can be achieved in Human Keratinocyte lines transformed with HPV16 (HKc/HPV16) and their respective HKc/DR cells lines, and to assess the effect of p53 knock-down on the response of HKc/HPV16 to UV.

Rights

© 2015, Nella Christie Delva

Download

Included in

Biology Commons

Share

COinS