Semester

Spring

Date of Graduation

2019

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Not Listed

Committee Chair

J. Michael Ruppert

Committee Co-Chair

Laura F. Gibson

Committee Member

Laura F. Gibson

Committee Member

John B. Barnett

Committee Member

Peter Stoilov

Committee Member

William P. Petros

Abstract

Non-coding RNAs (NcRNAs), such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been found to be involved in a variety of critical biological processes, and dysregulation of ncRNAs have been involved with several human diseases including cancer.

High-risk human papillomavirus (HPV) infection is one of the first events in the process of carcinogenesis in cervical and a subset of head and neck cancers. The expression of the viral oncoproteins E6 and E7 is essential in this process by inactivating the tumor suppressor proteins p53 and Rb, respectively, in addition to their interactions with other host proteins and regulation of ncRNAs. Our group identified novel regulation of host lncRNAs by HPV oncoprotein E6. More specifically, we discovered that a lncRNA known as FAM83H-AS1 is involved with proliferation, migration, and apoptosis in cervical cells, and high expression of this lncRNA correlates with poor overall cervical cancer patient survival. FAM83H-AS1 is a nuclear RNA, and mechanistically it is regulated through the E6-p300 pathway in a p53-independent manner. These findings provide knowledge of a specific lncRNA that could be studied further as a biomarker and/or therapeutic target not only in HPV-related cancers but also in other types of cancers where FAM83H-AS1 expression is dysregulated.

In parallel with these studies, our group identified a specific subgroup of miRNAs that are induced during quiescence and processed by a non-canonical biogenesis pathway by using primary human cells. miRNA expression is dysregulated when cells undergo a reversible state of growth arrest known as quiescence. These primary (pri-)miRNAs are modified with a 2,2,7-trimethylguanosine (TMG)-cap such that they are processed downstream in an Exportin-1 (XPO1)-dependent manner, independent of the canonical Exportin-5 (XPO5) protein used for exportation to the cytoplasm. The discovery of a new alternative miRNA pathway in quiescent primary human cells opens the door to future studies in other types of cells, such as stem cells and cancer stem cells, where the state of quiescence is important in their biological functions.

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