Zhejiang Province Key Laboratory of Anti-cancer Drug Research, Institute of Pharmacology and Toxicology, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Hangzhou No. 14 Middle School, Hangzhou 310006, China.
J Pharmacol Sci. 2018 Oct;138(2):89-95. doi: 10.1016/j.jphs.2018.07.013. Epub 2018 Sep 22.
Tumor-associated macrophages (TAMs) has been regarded as the most prominent component in tumor microenvironment. The correlation between TAM density and poor prognosis in Hepatocellular carcinoma (HCC) patients suggests a supportive role for TAMs in tumor progression. Here we employed a co-culture system to interrogate the molecular link between Yes-Associated Protein (YAP) and TAMs chemotaxis in HCC cells. We found that YAP activation was critical for the recruitment of TAMs towards HCC cells. Furthermore, cytokine array and quantitative RT-PCR analyses showed that IL-6 secreted by YAP-activated HCC cells might induce the TAMs recruitment. Interrupting YAP function by statins, the inhibitors of hydroxymethylglutaryl-CoA reductase, could robustly suppress the chemotaxis of TAMs. Together with our findings that the expression levels ofIL-6inhumanHCC tumors were highly correlated with the prognosis of HCC patients, the current study highlight the possibility of improving HCC treatment by targeting YAP-IL-6 mediated TAMs recruitment.
肿瘤相关巨噬细胞（TAMs）已被认为是肿瘤微环境中最显著的组成部分。TAM 密度与肝细胞癌（HCC）患者预后不良之间的相关性表明，TAMs 在肿瘤进展中起支持作用。在这里，我们采用共培养系统来探究 Yes 相关蛋白（YAP）与 HCC 细胞中 TAMs 趋化性之间的分子联系。我们发现 YAP 激活对于 TAMs 向 HCC 细胞的募集至关重要。此外，细胞因子阵列和定量 RT-PCR 分析表明，YAP 激活的 HCC 细胞分泌的白细胞介素 6（IL-6）可能诱导 TAMs 的募集。通过他汀类药物（羟甲基戊二酰辅酶 A 还原酶抑制剂）阻断 YAP 功能，可以强烈抑制 TAMs 的趋化性。结合我们发现人 HCC 肿瘤中 IL-6 的表达水平与 HCC 患者的预后高度相关，本研究强调了通过靶向 YAP-IL-6 介导的 TAMs 募集来改善 HCC 治疗的可能性。
