Division of General Surgery, Peking University First Hospital, Beijing, China.
Central Laboratory, Peking University First Hospital, Beijing, China.
Cancer Lett. 2019 Dec 1;466:49-60. doi: 10.1016/j.canlet.2019.09.006. Epub 2019 Sep 19.
Acquired resistance to 5-fluorouracil (5-FU) is a major barrier to benefit from chemotherapy in colon cancer patients. Hydrogen sulfide (HS), 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 HS 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 HS synthesis significantly sensitized colon cancer cell lines to 5-FU both in vitro and in vivo. Decreasing HS 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 HS synthesis significantly decreased the expression of EREG and TYMS. These results demonstrate that inhibiting HS synthesis can reverse the acquired resistance to 5-FU in colon cancer cells.
获得性对 5-氟尿嘧啶（5-FU）的耐药性是结肠癌患者从化疗中获益的主要障碍。硫化氢（HS）主要由胱硫醚-β-合酶（CBS）产生，据报道可促进结肠癌细胞的增殖和迁移。在这项研究中，研究了抑制 HS 合成对结肠癌细胞系对 5-FU 敏感性的影响。在在线数据库和组织微阵列中验证了 CBS 的表达增加。抑制 HS 合成在体外和体内均显著增强了结肠癌细胞系对 5-FU 的敏感性。利用 shRNA 慢病毒降低 HS 合成显著逆转了对 5-FU 的获得性耐药性。进行了 microRNA 测序，发现 miR-215-5p 是 CBS 敲低后表达水平变化最大的 miRNA 之一。表皮调节素（EREG）和胸苷酸合成酶（TYMS）被预测为 miR-215-5p 的潜在靶标。降低 HS 合成显著降低了 EREG 和 TYMS 的表达。这些结果表明，抑制 HS 合成可以逆转结肠癌细胞对 5-FU 的获得性耐药性。
