MicroRNAs as Targets for the Treatment of Hepatocellular Carcinoma We have investigated the role of alterations in microRNA expression in hepatocellular carcinoma (HCC) and cirrhosis versus normal liver and whether alterations in the expression of unique microRNAs are associated with metastatic HCC and correlates with prognosis and recurrence. We have discovered microRNA expression signatures specific for hepatocellular carcinomas and for metastatic disease. In this project we propose to assess the role of alterations in several microRNAs in the pathogenesis of HCC to define microRNAs that are suitable targets for therapeutic intervention. We will focus on miR181a/b, miR21, miR25, miR221/222 and miR155 that are overexpressed in HCC and miR145, miR215, miR125, miR126, miR192, miR223, and miR122a, that are down-regulated in HCC. We also found microRNAs that potentially target the 3'UTR of the maintenance (DNMT1) and the de novo (DNMT3A, 3B) DNA methyltransferases. We will assess whether loss of these microRNAs result in overexpression of DNMTs and silencing of tumor suppressor genes associated to hepatocellular carcinogenesis. At the same time we will sequence the 3'UTRs of the DNA methyltransferases DNMT1, DNMT3A and 3B to determine whether mutations in target sequences of microRNAs result in their upregulation. Thus the proposed study intends to establish the role of alterations in microRNA expression in the initiation and progression of hepatocellular carcinoma and to validate microRNAs as targets for therapeutic intervention in hepatocellular carcinoma.

Public Health Relevance

- Public Health We intend to develop microRNA based therapies for hepatocellular carcinoma (HCC), an extremely aggressive and lethal malignancy. We have defined deregulation of specific microRNAs in HCC. We intend to exploit this knowledge to develop targeted therapies of HCC based on the correction of microRNA dysregulation.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA135030-04
Application #
8197243
Study Section
Molecular Oncogenesis Study Section (MONC)
Program Officer
Sorg, Brian S
Project Start
2009-01-01
Project End
2013-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
4
Fiscal Year
2012
Total Cost
$516,062
Indirect Cost
$172,021
Name
Ohio State University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Laganà, Alessandro; Acunzo, Mario; Romano, Giulia et al. (2014) miR-Synth: a computational resource for the design of multi-site multi-target synthetic miRNAs. Nucleic Acids Res 42:5416-25
Pineau, Pascal; Volinia, Stefano; McJunkin, Katherine et al. (2010) miR-221 overexpression contributes to liver tumorigenesis. Proc Natl Acad Sci U S A 107:264-9
Garofalo, Michela; Di Leva, Gianpiero; Romano, Giulia et al. (2009) miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation. Cancer Cell 16:498-509