Sox9/INHBB axis-mediated crosstalk between the hepatoma and hepatic stellate cells promotes the metastasis of hepatocellular carcinoma.

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. Copyright © 2020 Elsevier B.V. All rights reserved.

Citation

Yu Chen, Baowei Qian, Xiaolin Sun, Zhiqian Kang, Zhen Huang, Zhi Ding, Lei Dong, Jiangning Chen, Junfeng Zhang, Yuhui Zang. Sox9/INHBB axis-mediated crosstalk between the hepatoma and hepatic stellate cells promotes the metastasis of hepatocellular carcinoma. Cancer letters. 2021 Feb 28;499:243-254

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PMID: 33246092

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