Inhibition of hydrogen sulfide synthesis reverses acquired resistance to 5-FU through miR-215-5p-EREG/TYMS axis in colon cancer cells

Acquired resistance to 5-fluorouracil (5-FU) is a major barrier to benefit from chemotherapy in colon cancer patients. Hydrogen sulfide (H2S), mainly produced by cystathionine-β-synthase (CBS), has been reported to promote the proliferation and migration of colon cancer cells. In this study, the effect of inhibiting H2S synthesis on the sensitivity of colon cancer cell lines to 5-FU was investigated. Increased expression of CBS was validated in online database and tissue microarrays. Inhibiting H2S synthesis significantly sensitized colon cancer cell lines to 5-FU both in vitro and in vivo. Decreasing H2S synthesis utilizing shRNA lentiviruses significantly reversed the acquired resistance to 5-FU. MicroRNA sequencing was performed and miR-215-5p was revealed as one of the miRNAs with most significantly altered expression levels after CBS knock down. Epiregulin (EREG) and thymidylate synthetase (TYMS) were predicted to be potential targets of miR-215-5p. Decreasing H2S synthesis significantly decreased the expression of EREG and TYMS. These results demonstrate that inhibiting H2S synthesis can reverse the acquired resistance to 5-FU in colon cancer cells.