Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
Clinical Medicine Research Center, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China.
Cancer Lett. 2020 Jul 1;481:32-44. doi: 10.1016/j.canlet.2020.03.027. Epub 2020 Apr 1.
Enhancing the sensitivity of hepatocellular carcinoma (HCC) cells to sorafenib (SFN) is an essential clinical bottleneck to be solved. Here we report that the expression of CD47 negatively correlated with HCC sensitivity to SFN. The microbiota-derived Staphylococcal superantigen-like protein 6 (SSL6) inhibited CD47 and promoted SFN-induced apoptosis of HCC cells Huh-7 and MHCC97H. Mechanistically, the sensitivity of HCC cells to SFN was inhibited by elevated Warburg effect (glycolysis), and SSL6 down-regulated PI3K/Akt-mediated glycolysis by blocking CD47. Knockdown of CD47 also dampened glycolysis and sensitized HCC cells to SFN. Moreover, SFN-resistant HCC cells exhibited enhanced glycolysis and CD47 expression. SSL6 significantly re-sensitized the resistant HCC cells to SFN. More importantly, we identified the anti-tumor effect of SSL6 in combination with SFN in HCC-bearing mice. Our results clarify the mechanism by which SSL6 enhances SFN sensitivity in HCC cells, providing a molecular basis for combination targeted therapy with microbiota-derived SSL6 to treat HCC.
提高肝细胞癌（HCC）细胞对索拉非尼（SFN）的敏感性是一个亟待解决的临床难题。本研究报告称，CD47 的表达与 HCC 对 SFN 的敏感性呈负相关。来源于微生物组的葡萄球菌超抗原样蛋白 6（SSL6）抑制 CD47 并促进 HCC 细胞 Huh-7 和 MHCC97H 对 SFN 诱导的细胞凋亡。从机制上讲，HCC 细胞对 SFN 的敏感性受到增强的瓦博格效应（糖酵解）的抑制，而 SSL6 通过阻断 CD47 抑制了 PI3K/Akt 介导的糖酵解。CD47 的敲低也抑制了糖酵解并使 HCC 细胞对 SFN 敏感。此外，SFN 耐药的 HCC 细胞表现出增强的糖酵解和 CD47 表达。SSL6 显著重新使耐药 HCC 细胞对 SFN 敏感。更重要的是，我们在 HCC 荷瘤小鼠中鉴定了 SSL6 与 SFN 联合的抗肿瘤作用。我们的研究结果阐明了 SSL6 增强 HCC 细胞中 SFN 敏感性的机制，为利用微生物组衍生的 SSL6 进行联合靶向治疗 HCC 提供了分子基础。
