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Title Tp53 and Hras Influence on HPV16 E7 Expression in HPV16-Transformed Human Keratinocytes
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Publication Date
Degree MSin Biological Sciences
Discipline/Department Biological Sciences
Degree Level masters
University/Publisher University of South Carolina
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 <strong>HPV-inactive tumors </strong>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.
Subjects/Keywords Biology; Life Sciences; Tp53; Hras; HPV16; kratinocytes; head and neck squamous carcinoma; HPV
Contributors Lucia Pirisi-Creek
Rights Open Access Thesis
Country of Publication us
Record ID oai:scholarcommons.sc.edu:etd-4089
Repository south-carolina
Date Retrieved
Date Indexed 2018-11-21
Created Date 2015-01-01 08:00:00

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…acquisition of independence from E6/E7 ..........12 Figure 2.6, In vitro model of HPV16-mediated carcinogenesis .......................................16 Figure 3.7. Hairpin structure schematic…

…35 Figure 3.15, p53 ELISA results in HKc/HPV16 non-transfected UV treated cells ...........36 Figure 3.16. p53 ELISA results in HKc/HPV16 non-transfected UV treated cells ...........37 Figure 3.17, Tp53 ELISA results in the HKc/HPV16d-1 cell line…

…x28;D1++) .......................39 Figure 3.18, UV treated HKc/HPV16 cell morphology ....................................................40 Figure 3.19, HKc/DR Similar to our HKc/HPV16 p53i-sh transfected cells line .............41 ix Figure…

…keratinocytes HKc/DR ..................... differentiation resistant, HPV16-transformed human keratinocytes HKc/HPV16 ................................... human keratinocytes immortalized with HPV16 DNA HKc/HPV16d-1........ human keratinocytes from donor 1…

…immortalized with HPV16 DNA HNSCC ...................................................................... head and neck squamous Carcinoma HPV.................................................................................................. Human papillomavirus…

…have been identified only 40 types are oncogenic (13,16), HPV16 is one of the most causative agents leading to invasive cancers, it was also found be associated with HNSCC (13,14). 4 Lehoux et al. 2009. Figure 1.2 Papilloma virus…

…differentiated upper layers, then release. 5 1.3 P53 and RB pathway in HPV16-mediated carcinogenesis Tp53 is tumor suppressor gene that plays an important role in cell cycle and apoptosis. It is also called the “guardian” of the genome. The p53 protein…

…These two tumor suppressor genes were found to have strong association with various type of cancer including HNSCC. In the case of HPV16-mediated carcinogenesis, the tumors are driven by the E6 and E7 viral oncoproteins (19, 20). E6 and E7 are…

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