Defense Date

2012

Document Type

Thesis

Degree Name

Master of Science

Department

Physiology

First Advisor

Dr. Hiroshi Miyazaki

Abstract

Head and Neck Squamous Cell Carcinoma (HNSCC) is an epithelial skin cancer of the upper aerodigestive tract, and is the sixth most common malignancy in the U.S. HNSCC patients undergoing chemotherapy commonly develop anemia, a condition in which the body lacks mature red blood cells (RBCs). Erythropoietin (EPO) is a systemically circulating hormone in the body that regulates the production of RBCs and is applied to treat anemia. Recently, several studies implicated shortened life expectancy of cancer patients by EPO administration. It may be due to an unexpected activation of survival and proliferation pathways of cancer cells by EPO because of the presence of ectopically expressed erythropoietin receptor (EPOR) on the surface of cancer cells. The current study tests the biological effects of EPO and EPOR in HNSCC. A shRNA-mediated knockdown of the EPOR gene was applied to two specific cell lines, HN4 and its metastatic derivative HN12. Knockdown of EPOR decreased proliferation in both HN4 and HN12 cells. To our surprise, application of EPO to HN12 control cell line downregulated proliferation in these high EPOR-expressing cells. Conversely, EPO increased proliferation in a breast cancer cell line, MCF-7. Although EPO greatly impacted HNSCC proliferation, no significant difference was found in migration of these cells upon its application. It was indicated that the pathway responsible for proliferative effects in HNSCC from EPOR association could be due to activation of the PI-3/Akt pathway, judged by its phosphorylation of AKT. However, we need to further elucidate the contradictive biological mechanisms of downregulation of HNSCC and upregulation of MCF-7 proliferation. We also need to expand the number of screened cell lines and confirm the relevance of our observation. Collected together, these findings confirm the hypothesis that EPO and EPOR can impact HNSCC tumor progression, and that their effects may vary among cancer types. These results draw attention to the possible detrimental use of EPO in cancer treatment, and its administration therefore, should be reevaluated.

Rights

© The Author

Is Part Of

VCU University Archives

Is Part Of

VCU Theses and Dissertations

Date of Submission

August 2012

Included in

Physiology Commons

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