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

Abstract

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.

• Authors: Yu Chen, Baowei Qian, Xiaolin Sun, Zhiqian Kang, Zhen Huang, Zhi Ding, Lei Dong, Jiangning Chen, Junfeng Zhang, Yuhui Zang
• Journal: Cancer letters (Cancer Lett) Vol. 499 Pg. 243-254 (02 28 2021) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 33246092 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Elsevier B.V. All rights reserved.

Chemical References

• INHBB protein, human
• SOX9 Transcription Factor
• SOX9 protein, human
• Smad Proteins
• activin B
• Activins
• Inhibin-beta Subunits

Topics

• Activins (metabolism)
• Animals
• Carcinoma, Hepatocellular (genetics, secondary)
• Cell Proliferation (genetics)
• Disease Progression
• Gene Expression Regulation, Neoplastic
• Gene Knockdown Techniques
• Hep G2 Cells
• Hepatic Stellate Cells (pathology)
• Humans
• Inhibin-beta Subunits (genetics)
• Liver (cytology, pathology)
• Liver Cirrhosis (genetics, pathology)
• Liver Neoplasms (genetics, pathology)
• Male
• Mice
• Paracrine Communication (genetics)
• SOX9 Transcription Factor (genetics, metabolism)
• Signal Transduction (genetics)
• Smad Proteins (metabolism)
• Tumor Microenvironment (genetics)
• Up-Regulation
• Xenograft Model Antitumor Assays