Date of Award

1-1-2011

Document Type

Dissertation

Degree Name

Ph.D.

Organizational Unit

College of Natual Science and Mathematics

First Advisor

Naushad Ali

Second Advisor

Robert Dores

Third Advisor

Joseph Angleson

Fourth Advisor

Daniel Linseman

Keywords

Hepatitis C virus, Liver cancer, Stem cells

Abstract

Hepatitis C virus (HCV) is an important human pathogen that causes chronic hepatitis cirrhosis, steatosis and hepatocellular carcinoma (HCC) worldwide. Although current FDA-approved drugs are partially effective in the treatment of HCV, methods for cure and vaccine against the virus are still awaited. My thesis work presented here is focused on finding mechanism (s) of HCV-induced hepatocarcinogenesis and devising novel means to combat the HCV infection.

Herein, we have shown that long-term HCV expression results in the acquisition of cancer stem-like cells (CSCs) traits in liver derived cell lines. These traits include enhanced expression of putative stem cell markers DCAMKL-1, Lgr5, CD133 and c-Myc. We also showed that HCV replication is severely impaired by siRNA-led depletion of the microtubule filaments (MTFs)-associated DCAMKL-1. The cholesterol-lowering drug, fluvastatin, reduces DCAMKL-1 RNA and affects its protein localization on the microtubule filaments resulting in marked reduction in the viral RNA and protein abundance. The mouse xenografts, liver biopsy and tissue microarrays unveiled overexpression of DCAMKL-1 during chronic HCV infection and cirrhosis, and in the HCV-replicon expressing cells. We further demonstrate that HCV results in excessive expression of a-fetoprotein, cytokeratin-19, c-Myc, and c-Src, and activation of b-catenin pathway in the absence of Wnt ligand. The result presented here implicates a novel cellular internal ribosome entry site (IRES) element in the c-Src mRNA responsible for the overexpression of c-Src proto-oncogene under stressed conditions such as HCV infection.

These results presented here collectively suggest that HCV exhibits ability to induce reprogramming and/or retrodifferentiation of the host cells and further revealed a novel HCV-(DCAMKL-1)-MTF-CSCs axis that might be responsible for the HCV RNA abundance in the infected cells and HCV-induced hepatocarcinogenesis. The putative stem cell marker, DCAMKL-1, represents a novel cellular target for combating HCV and liver cancer. The concept of a `virus-induced stem cell traits' can also be extrapolated to study diseases caused by other RNA viruses.

Publication Statement

Copyright is held by the author. User is responsible for all copyright compliance.

Rights Holder

Heba Samir Esmaeil Allam

Provenance

Received from ProQuest

File Format

application/pdf

Language

en

File Size

183 p.

Discipline

Microbiology, Molecular biology, Cellular biology

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