Research Abstracts Online
January 2010 - March 2011
University of Minnesota Twin Cities
of Laboratory Medicine and Pathology
PI: Subbaya Subramanian
MicroRNA Regulatory Networks in Cancer
Abstract early growth response 1 (EGR1), a tumor suppressor gene, is downregulated in many cancer types. Clinically, loss of EGR1 translates to increased tumor transformation and subsequent patient morbidity and mortality. In synovial sarcoma, it was shown that the SS18-SSX fusion protein, through a direct association with the EGR1 promoter, represses EGR1. However, the mechanism through which EGR1 is downregulated in other tumor types is still not clear.
This group’s studies indicate that EGR1 is regulated by miR-183 in multiple tumor types including synovial sarcoma, rhabdomyosarcoma (RMS), and colon cancer. Using an integrative network analysis, they discovered that miR-183 is significantly overexpressed in these tumor types as well as in corresponding tumor cell lines. Bioinformatic analyses suggested that miR-183 could target EGR1 mRNA and this specific interaction was validated in vitro. Subsequent antimiR based knockdown studies of miR-183 in synovial sarcoma, RMS, and colon cancer cell lines revealed deregulation of a miRNA network composed of miR-183–EGR1–PTEN in these tumors. Integrated miRNA and mRNA based genomic analyses indicated that miR-183 is an important contributor to cell migration in these tumor types and this result was functionally validated to be occurring via an EGR1 based mechanism. These findings have significant implications in the mechanisms underlying EGR1 regulation in cancers. miR-183 has a potential oncogenic role through the regulation of two tumor suppressor genes, EGR1 and PTEN and the deregulation of this fundamental miRNA regulatory network may be central to many tumor types.
Rasik Hemant Phalak, Graduate Student
Aaron Sarver, Research Associate
Venugopal Thayanithy, Research Associate