Projects

Role of miRNAs in cancer and modulation of oncogenes by natural products

Cancer known medically as a malignant neoplasm, is a broad group of diseases involving unregulated cell growth. Understanding the mis-regulation of molecular mechanisms leading to cancer has been the primary method of discovering new drug targets. MicroRNAs (miRNAs) are small, noncoding RNAs with important functions in development, cell differentiation, and regulation of cell cycle and apoptosis. miRNA expression is dis-regulated in cancer by a variety of mechanisms including amplification, deletion, mutation, and epigenetic silencing. Several studies have now shown that miRNAs are involved in the initiation and progression of cancer. Numerous studies have shown that miRNA expression profiles provide valuable molecular signatures for different tissues and human cancers that could be used for diagnostic applications, prognosis and maybe even therapy. Individual miRNAs may function as tumor suppressor genes by regulating the expression of proto-oncogenes such as Ras, or conversely examples such as miR-21 act as oncogenes when over-expressed, by down-regulating expression of pro-apoptotic genes. Natural products are known to decrease oncogenes and genes that are over expressed in cancer cells like MMPs, EGFR and ER. For example, MMP-2 levels or activity, or both are being modulated by natural products such as anacardic acid, curcumin, epigallocatechin, resveratrol, myricetin, obovatal and ellagic acid. The key question asked in this study will be whether isolated natural products (like anacardic acid) will inhibit the expression of different oncogenes at the transcriptional (promoter), or at the post-transcriptional (miRNA) level and whether we can find more miRNAs that are involved in the regulation of carcinogenesis. MDA-MB-231 cells were tranduced with hsa-mir-491 lenti-viral vector constructs to establish stable transductants that over express the miRNA. qRT-PCR studies showed a clear down regulation of MMP-9 expression in miRNA over expressing cells lines as compared to the control MDA-MB-231 cells. Additionally, the hsa-miR-491 over expressing stable cell line also showed a significantly low migratory potential  providing the first evidence for inhibition of MMP-9 by hsa-mir-491 in breast cancer cells.