Investigation of Hmga2-Microrna Regulatory Network to Tune Oncogenesis

Colorectal cancer (CRC) is one of the leading causes of cancer death worldwide with increasing incidence and mortality in the developed countries. Oncogenes and microRNAs (miRNAs) are revealed to be deregulated and regulating key signaling pathways in CRC. High-mobility group AT-hook 2 (HMGA2), with both activation and inhibition transcriptional activity, is a developmental regulator essential for adipogenesis and mesenchymal differentiation and an oncogenic promoter for tumorigenesis. Previously, we revealed that as a direct upstream inhibitory regulator of miR-194, overexpression of HMGA2 reduced miR-194 expression and biological activity, whereas re-expressing miR-194 in cells with high levels of HMGA2 impaired the effects of HMGA2, compromising cell survival, the epithelial-mesenchymal transition process, and drug resistance. Together with bioinformatics analysis, we postulate that HMGA2 plays a unique role in CRC development through reducing tumor suppressor (TS) miRNA expression. Although a negative regulation on miR-194 expression of HMGA2 has been identified, how HMGA2 serves as an inhibitory regulator on miR promoters remained unclear. The major objective of this proposal is to tackle the transcriptional regulatory components on promoters of HMGA2 inhibited miRNAs, such as miR-194, to specify the “readers” for HMGA2 regulation on TS miRs. The results will conceptualize the unique niche of HMGA2 on locus-specific regulation with in-depth understanding of how inhibition of TS miR is achieved by HMGA2 and can be translated in managing tumorigenesis of CRC in the future. The proposal is designed for three-year investigation, and the specific aims are:Aim 1. To identify the TS miRNAs inhibited by HMGA2 (1st Year)Aim 2. To profile the protein regulome on promoters of HMGA2-inhibited miRs (1st~2nd Year)Aim 3. To inspect protein-protein interaction of HMGA2 from specific promoters (2nd~3rd Year)Aim 4. To construct and verify the models for HMGA2 inhibition on TS miRs (3rd Year)