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.

肿瘤周围组织中肝星状细胞（HSC）的激活和肝纤维化有助于肝细胞癌（HCC）的发展。但是，肝癌和肿瘤周围HSC之间串扰的潜在机制仍然难以捉摸。我们发现Sox9 / INHBB轴在肝癌中上调，并与肿瘤转移有关。使用功能获得和丧失功能的方法，我们发现Sox9 / INHBB轴通过激活肿瘤周围的HSC促进原位HCC肿瘤的生长和转移。从机制上讲，Sox9通过直接结合其增强子来诱导INHBB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信号减弱了肿瘤周围组织的纤维化反应，并降低了转移的发生率。最后，临床分析表明HCC标本中Sox9与INHBB表达之间呈正相关，并确定Sox9 / INHBB轴为肝纤维化的阳性调节剂。总之，Sox9 / INHBB轴介导的肝癌细胞与HSC之间的串扰诱导了有利于HCC转移的肥沃环境，从而成为潜在的治疗靶点。