The proposal is based on earlier studies describing a novel "on-off" reversible switch mechanism that regulates transcription of multiple genes, mainly proto-oncogenes that control cell division and tumorigenesis. The mechanism involves repression by PSF protein and reversal of repression by endogenous RNAs that bind and release PSF from a gene. The general aim of the R21 proposal is to determine whether the genomic RNA of hepatitis D virus (HDV gRNA) has the same tumorigenic function as endogenous PSF-binding RNAs, involving binding to PSF and reversing repression of proto-oncogenes. Epidemiological studies suggest that infection by HDV, and also by HCV, can cause HCC, and co-infection with HBV is required to provide help for producing HDV particles, contradicting the prevailing view that HBV causes HCC. The epidemiological evidence is bolstered by molecular evidence showing that HDV gRNA binds preferentially to PSF protein in vitro, and by functional evidence showing that transfection of NIH3T3 cells with a HDV gRNA transgene results in transformation of the NIH3T3 cells to tumorigenic cells. Encouraged by these seminal findings, we propose the following experiments. (i) Test for binding of HDV gRNA to PSF protein and induced transcription of the proto- oncogene Rab23 in NIH3T3 cells transfected with a HDV gRNA transgene;(ii) Test for formation of tumors in a mouse liver by transfecting a HDV gRNA transgene into the liver. We expect these experiments will provide further support for the proposed tumorigenic role of HDV gRNA in the etiology of HCC and lead to new molecular targets for diagnosing and treating HCC induced by HDV infection.

Public Health Relevance

The proposal will test a novel mechanism that generates hepatocellular carcinoma (HCC) resulting from infection with hepatitis D virus (HDV), which contradicts the prevailing view that HBV causes HCC. We expect the results will identify new molecular targets for diagnosis and therapy of HCC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA141105-02
Application #
8333370
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
2011-09-15
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
2
Fiscal Year
2012
Total Cost
$180,616
Indirect Cost
$71,866
Name
Yale University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520