Abstract 2077: Downregulation of miR-21 induces differentiation of chemo-resistant colon cancer cells and enhances susceptibility to therapeutic regimens.

Abstract

Abstract MicroRNAs (miRNAs) are endogenous posttranscriptional modulators that negatively control the expression of their target genes and play an important role in the development and progression of colorectal carcinoma. In particular, microRNA-21 (miR-21), whose expression is greatly increased in chemotherapy-resistant (CR) colon cancer cells that are enriched in undifferentiated cancer stem/stem-like cells (CSCs/CSLCs). We hypothesize that miR-21 plays a critical role in regulating differentiation of colon cancer (CR cells). Indeed, we observed that downregulation of miR-21 in CR colon cancer HCT-116 cells by anti-sense-miR-21 induced differentiation, as evidenced by marked increases in CK-20 (cytokeratin-20) expression and alkaline phosphatase activity. These changes were accompanied by a significant reduction in the expression of colon CSC/CSLCs marker CD44, colonospheres formation and TCF/LEF activity and increased expression of the pro-apoptotic gene PDCD4. Induction of differentiation greatly increased the sensitivity of CR cells to the growth inhibitory effects of all three regimens tested: 5- FU+ Oxaliplatin (FUOX), difluorinated curcumin (CDF), an analog of curcumin and the combination of CDF and FUOX. However, the magnitude of inhibition of growth by either CDF (75%) alone or CDF + FUOX (80%) was much higher than that observed with FUOX (40%). Growth inhibition by CDF and CDF + FUOX in differentiating CR colon cancer cells was associated with a 98-99% reduction in the expression of CD44 and EGFR. The current observation suggest that CDF as well as CDF + FUOX are highly effective in inhibiting growth and reducing colon CSCs/CSLCs in anti-miR-21-induced differentiating CR colon cancer cells, which supports our contention that differentiating cells become susceptible to conventional and non-conventional therapeutic regimen. Citation Format: Yingjie Yu, Fazlul H. Sarkar, Adhip P.N. Majumdar. Downregulation of miR-21 induces differentiation of chemo-resistant colon cancer cells and enhances susceptibility to therapeutic regimens. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2077. doi:10.1158/1538-7445.AM2013-2077