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.
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.
| Di Leva, Gianpiero; Cheung, Douglas G; Croce, Carlo M (2015) miRNA clusters as therapeutic targets for hormone-resistant breast cancer. Expert Rev Endocrinol Metab 10:607-617 |
| 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 |
| Fabbri, Muller; Paone, Alessio; Calore, Federica et al. (2012) MicroRNAs bind to Toll-like receptors to induce prometastatic inflammatory response. Proc Natl Acad Sci U S A 109:E2110-6 |
| 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 |
| Valeri, Nicola; Gasparini, Pierluigi; Fabbri, Muller et al. (2010) Modulation of mismatch repair and genomic stability by miR-155. Proc Natl Acad Sci U S A 107:6982-7 |
| 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 |
