Hepatitis C Virus-Induced Hepatocellular Carcinoma: Cancer Stem Cell and Gene Therapy

<p>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.</p> <p>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.</p> <p>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.</p>

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Year dc:date.available

2011

Author dc:creator

• Allam, Heba Samir Esmaeil

Contributors dc:contributor

• Naushad Ali
• Robert Dores
• Joseph Angleson
• Daniel Linseman

• Hepatitis C virus
• Liver cancer
• Stem cells
• Biology
• Life Sciences

Statement dc:rights

• <p>Copyright is held by the author. User is responsible for all copyright compliance.</p>

Language dc:language

en

Repository record dc:identifier

https://digitalcommons.du.edu/etd/746

OAI identifier oai:identifier

oai:digitalcommons.du.edu:etd-1745