Sox9/INHBB axis-mediated crosstalk between the hepatoma and hepatic stellate cells promotes the metastasis of hepatocellular carcinoma
Sox9/INHBB axis-mediated crosstalk between the hepatoma and hepatic stellate cells promotes the metastasis of hepatocellular carcinoma
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Sox9/INHBB轴介导的肝癌和肝星状细胞之间的串扰促进肝细胞癌的转移。
DOI：
10.1016/j.canlet.2020.11.025
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发表时间：
2021-02-28
期刊：
影响因子：
9.7
通讯作者：
Zang, Yuhui
中科院分区：
文献类型：
--
作者：
Chen, Yu;Qian, Baowei;Zang, Yuhui
肝星状细胞(HSCs)的激活和瘤周组织中的肝纤维化参与了肝细胞癌的进展。然而，肝癌和癌旁肝星状细胞之间相互干扰的机制仍然不清楚。我们发现Sox9/INHBB轴在肝细胞癌中上调，并与肿瘤转移有关。利用功能获得和功能丧失的方法，我们发现Sox9/INHBB轴通过激活瘤周HSCs促进原位肝细胞癌的生长和转移。在机制上，Sox9通过直接与其增强子结合来诱导INHBB的表达，从而帮助肝癌细胞分泌激活素B，进而通过激活素B/Smad信号促进周围HSC的激活。此外，抑制激活素B/Smad信号通路可以减弱瘤周组织的纤维化反应，降低转移的发生率。最后，临床分析表明，Sox9和INHBB在肝细胞癌标本中的表达呈正相关，并确认Sox9/INHBB轴是肝纤维化的正调节因子。总之，Sox9/INHBB轴介导的肝癌细胞和HSCs之间的串扰诱导了有利于肝癌转移的肥沃环境，从而显示出潜在的治疗靶点。
The activation of hepatic stellate cells (HSCs) and liver fibrosis in the peri-tumoral tissue contributes to the progression of hepatocellular carcinoma (HCC). However, the mechanisms underlying the crosstalk between hepatoma and peri-tumoral HSCs remain elusive. We found that the Sox9/INHBB axis is upregulated in HCC and is associated with tumor metastasis. Using gain- and loss-of-function approaches, we revealed that the Sox9/INHBB axis promotes the growth and metastasis of an orthotopic HCC tumor by activating the peri-tumoral HSCs. Mechanistically, Sox9 induces INHBB expression by directly binding to its enhancer, thus aiding in the secretion of activin B from hepatoma cells, and in turn, promoting the activation of the surrounding HSCs through activin B/Smad signaling. Furthermore, inhibition of activin B/Smad singaling attenuates the fibrotic response in the peri-tumoral tissue and decreases the incidence of metastasis. Finally, clinical analyses indicated a positive correlation between Sox9 and INHBB expression in HCC specimens and identified the Sox9/INHBB axis as a positive regulator of liver fibrosis. In conclusion, Sox9/INHBB axis-mediated crosstalk between hepatoma cells and HSCs induces a fertile environment favoring HCC metastasis, thereby exhibiting as a potential therapeutic target.