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.

中文翻译：

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微生物群衍生的SSL6通过下调糖酵解作用来增强肝细胞癌对索拉非尼的敏感性。

提高肝细胞癌（HCC）细胞对索拉非尼（SFN）的敏感性是需要解决的重要临床瓶颈。在这里我们报告CD47的表达与HCC对SFN的敏感性呈负相关。微生物来源的葡萄球菌超抗原样蛋白6（SSL6）抑制CD47，并促进SFN诱导的HCC细胞Huh-7和MHCC97H凋亡。从机制上讲，升高的Warburg效应（糖酵解）抑制了HCC细胞对SFN的敏感性，而SSL6通过阻断CD47下调了PI3K / Akt介导的糖酵解。击倒CD47还可以抑制糖酵解并使HCC细胞对SFN敏感。此外，耐SFN的HCC细胞表现出增强的糖酵解和CD47表达。SSL6显着使耐药HCC细胞对SFN重新敏感。更重要的是，我们鉴定了SSL6与SFN联合在荷癌小鼠中的抗肿瘤作用。我们的研究结果阐明了SSL6增强HCC细胞SFN敏感性的机制，为与微生物群衍生的SSL6联合靶向治疗肝癌提供了分子基础。