Many human cancers of epithelial origin are associated with overexpression of epidermal growth factor receptor (EGFR) family. In particular, ERBB2 and ERBB3 overexpression are linked with cancer development and poor prognosis. Except ERBB2/ERBB3 gene amplification, other mechanism(s) of ERBB2 and ERBB3 overexpression remains elusive. Recent studies show that aberrant expressions of miRNAs are associated with cancer development. To identify specific miRNAs for regulating ERBB2 and ERBB3 expression, we find that miR-199a and miR-125b directly target ERBB2 and ERBB3, and are downregulated in ovarian tissues and cancer cells. Elevated reactive oxygen species (ROS) have been observed in tumor growth and drug resistance. Interestingly we show that increased ROS downregulate miR-199a and miR-125b for inducing ERBB2 and ERBB3 expression. ERBB2 and ERBB3 in turn activate AKT/P70S6K1/HIF signaling leading to tumor growth and angiogenesis. This study provides a novel mechanism of ERBB2 and ERBB3 regulation by miR-199a and miR-125b and new concept of ROS for inducing ERBB2 and ERBB3 in tumor growth and angiogenesis; and establishes a rationale for using miR-199a and miR-125b mimics and ROS scavengers as new therapeutic agents in the future.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5046. doi:1538-7445.AM2012-5046