Date of Graduation
12-2013
Document Type
Dissertation (PhD)
Program Affiliation
Virology and Gene Therapy
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Feng Wang-Johanning
Committee Member
Gary L. Johanning
Committee Member
Dean G. Tang
Committee Member
Paul K. Y. Wong
Committee Member
Rick A. Finch
Committee Member
Victoria P. Knutson
Abstract
Human endogenous retroviruses (HERVs) are remnants from ancient retroviral infections, and most of them are inactive in normal tissues. One family of HERV, HERV-K, is found to be associated with multiple human cancers including breast cancer, pancreatic cancer and melanoma, but the causal relationship between HERV-K and cancer is still unclear. Increased expression of HERV-K in melanoma cells correlates with malignant transformation, while a serological response to HERV-K in breast cancer or melanoma patients correlates with survival probability. However, the mechanism behind these observations remains obscure. Our laboratory reported that anti-HERV-K envelope (Env) protein antibodies show antitumor potential in targeting breast tumors, indicating that HERV-K Env (Kenv) may play an important role in tumorigenesis. In this study, we used either knockdown (main focus) or over-expression approach, to investigate the role of Kenv in breast cancer, pancreatic cancer, and melanoma. Compared to the control cells, all the cancer cell lines transduced with Kenv-specific shRNA (shRNAenv) exhibited lower proliferation rates and lower tumorigenic potential in vitro, and some showed lower migration/ invasion rate. In vivo, tumorigenic potential of all the shRNAenv transduced cell lines was found to be reduced after inoculation into nude mice or NOD/SCID gamma (NSG) mice. Moreover, results from RNA Seq and Ingenuity Pathway Analysis (IPA) suggested the involvement of Kenv in the mevalonate pathway. In addition, introduction of Kenv into the premalignant human breast cell line MCF-10AT led to increased cell proliferation and colony formation. These results suggest that Kenv plays specific and important roles in progression of human breast cancer, pancreatic cancer, and melanoma.
Keywords
HERV-K, shRNA, human breast cancer, pancreatic cancer, melanoma