Date of Award

12-1-2018

Degree Name

Doctor of Philosophy

Department

Molecular Biology, Microbiology and Biochemistry

First Advisor

Davie, Judith

Abstract

Rhabdomyosarcoma (RMS) is a highly malignant form of pediatric cancer that originates from skeletal muscle cells. While the normal skeletal muscle cells are generated via a highly regulated process called myogenesis that depends on myogenic regulatory factors (MRFs), the RMS cells fail to differentiate as a result of impaired myogenesis due to abnormal MRF activity. We found that TCEA3 regulates myogenin (an essential MRF member) activity at the gene expression level. Our work showed that depletion of TCEA3 in normal myoblast cells results in an inhibition of differentiation and downregulation of MRFs. TCEA3 confers myogenic activity and results in differential recruitment of RNAPII to target promoters. While its role in ovarian cancer is well understood, its role in RMS is yet unclear. Thus, our work focused on investigating the role of TCEA3 in both the RMS subtypes, ARMS and ERMS. The results revealed that TCEA3 is downregulated in both the RMS subtypes, and further, its overexpression resulted in a decrease in migration and inhibition of anchorage-independent growth. It also is shown to induce apoptosis through intrinsic and extrinsic pathways. Additionally, we found that over expressing TCEA3 in RMS cells could sensitize these cells to chemotherapeutic drugs. Similar to TCEA3, TCEAL7 is downregulated in various types of cancers, including over 90% of ovarian epithelial cancers, and has shown tumor suppressing properties in ovarian cancers. Our work on RMS showed that TCEAL7 is highly deregulated in both of the immortal cell lines representing ARMS and ERMS, and highly expressed in the normal myoblast cells. Further, deletion of Tceal7 inhibits the proliferation of myoblasts suggesting that TCEAL7 is involved in promoting cell cycle progression in myoblast cells. Deletion of TCEAL7 also revealed a loss of MyHC expression upon differentiation and overexpression of TCEAL7 in RMS promotes differentiation in RMS cells. Additionally, the overexpression of TCEAL7 has led to a decrease in expression of the oncogene, Cyclin D1. Overall, the overexpression of TCEAL7 in RMS cell induces apoptosis and sensitizes cells to TRAIL induced cell apoptosis.

Available for download on Friday, February 19, 2021

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