Overcoming sternness and chemoresistance in colorectal cancer through miR-195-5p-modulated inhibition of notch signaling

MiR-195-5p has been shown to have a regulatory role in a variety of cancers. Its influence on colorectal cancer (CRC), however, has never been evaluated. In the present study, we found that miR-195-5p expression was significantly decreased as compared to paired, tumor-adjacent normal colorectal tissues. We demonstrated that miR-195-5p inhibited the stem-like capacity of CRC cells. We established 5-FU-resistant SW620 and HT-29 cell lines and performed a variety of functional assays following exposure to miR-195-5p and anti-miR-195-5p. In 5-FU-resistant cells, expression of miR-195-5p, P-gp and ABCG2 was decreased. MiR-195-5p significantly increased cancer cell apoptosis and decreased tumor sphere formation. In order to determine the mechanism by which miR-195-5p reduced CRC cell sternness and chemoresistance, we first identified potential targets of miR-195-5p. The 3' UTR of Notch signaling proteins Notch2 and RBPJ, which are essential genes in CRC cell sternness and chemoresistance, possessed double putative binding sites of miR-195-5p. qRT-PCR and western blot assays demonstrated significant decreases in Notch2 and RBPJ when CRC cell lines were exposed to miR195-5p and significant increases when exposed to anti-miR-195-5p. These findings indicate that miR-195-5p has the potential to improve standard therapeutic approaches to CRC. (C) 2018 Published by Elsevier B.V.