Abstract

Regulation of viral replication by microRNAs (miRNAs) and the role of microRNAs in cancer are two frontiers of research that have been under-investigated in the past. This research area has significant promise to greatly expand our molecular understanding of host-viral interactions and the process of malignant transformation. In the past year, our laboratory has pioneered studies on miRNAs in hepatocarcinogenesis and HBV replication. These investigations have identified miRNAs that are highly overexpressed or underexpressed in HCC, and identified candidate miRNAs that affect HBV replication. Several hypotheses regarding mechanisms of miRNA involvement in hepatocarcinogenesis and viral replication have arisen.
The specific aims are:
Aim 1. Investigate the effects of cellular miRNAs on HBV replication. We will test the hypothesis that cellular miRNAs act as cellular """"""""rheostats"""""""" that regulate the level of HBV replication. Our first studies will focus on miR-16, since it has a target site that is conserved among HBV genomes and supporting data suggest it is a negative regulator for HBV replication.
Aim 2. We will investigate the effects of miRNA on the early phases of HBV replication. We will test the hypothesis that cellular miRNAs with HBV target sites can inhibit or block early phases of HBV replication.
Aim 3 : We will investigate the role of miRNAs in hepatocarcinogenesis by testing how knocking out or inducing miRNAs affect the malignant HCC phenotype.
Aim 4 : We will identify miRNA targets in cancer cells and primary tumors, using a novel cloning/sequencing approach based on immunoprecipitation of RISC that contain miRNAs and their targets.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA037232-26
Application #
7810641
Study Section
Virology - A Study Section (VIRA)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1984-04-12
Project End
2012-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
26
Fiscal Year
2010
Total Cost
$508,016
Indirect Cost

  Institution

Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461

  Publications

Rogler, Charles E; Bebawee, Remon; Matarlo, Joe et al. (2017) Triple Staining Including FOXA2 Identifies Stem Cell Lineages Undergoing Hepatic and Biliary Differentiation in Cirrhotic Human Liver. J Histochem Cytochem 65:33-46
Rogler, Leslie E; Kosmyna, Brian; Moskowitz, David et al. (2014) Small RNAs derived from lncRNA RNase MRP have gene-silencing activity relevant to human cartilage-hair hypoplasia. Hum Mol Genet 23:368-82
Connolly, Erin C; Van Doorslaer, Koenraad; Rogler, Leslie E et al. (2010) Overexpression of miR-21 promotes an in vitro metastatic phenotype by targeting the tumor suppressor RHOB. Mol Cancer Res 8:691-700
Rogler, Charles E; Levoci, Lauretta; Ader, Tammy et al. (2009) MicroRNA-23b cluster microRNAs regulate transforming growth factor-beta/bone morphogenetic protein signaling and liver stem cell differentiation by targeting Smads. Hepatology 50:575-84
Connolly, Erin; Melegari, Margherita; Landgraf, Pablo et al. (2008) Elevated expression of the miR-17-92 polycistron and miR-21 in hepadnavirus-associated hepatocellular carcinoma contributes to the malignant phenotype. Am J Pathol 173:856-64
Rogler, Charles E; Zhou, Hong Chou; LeVoci, Lauretta et al. (2007) Clonal, cultured, murine fetal liver hepatoblasts maintain liver specification in chimeric mice. Hepatology 46:1971-8
Hajjou, Mustapha; Norel, Raquel; Carver, Robert et al. (2005) cDNA microarray analysis of HBV transgenic mouse liver identifies genes in lipid biosynthetic and growth control pathways affected by HBV. J Med Virol 77:57-65
Rogler, Charles E; Tchaikovskaya, Tatyana; Norel, Raquel et al. (2004) RNA expression microarrays (REMs), a high-throughput method to measure differences in gene expression in diverse biological samples. Nucleic Acids Res 32:e120
Plescia, C; Rogler, C; Rogler, L (2001) Genomic expression analysis implicates Wnt signaling pathway and extracellular matrix alterations in hepatic specification and differentiation of murine hepatic stem cells. Differentiation 68:254-69
Pourquier, P; Jensen, A D; Gong, S S et al. (1999) Human DNA topoisomerase I-mediated cleavage and recombination of duck hepatitis B virus DNA in vitro. Nucleic Acids Res 27:1919-25

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