STAT3 is Activated by CTGF-mediated Tumor-stroma Cross Talk to Promote HCC Progression

Cell Mol Gastroenterol Hepatol. 2023;15(1):99-119. doi: 10.1016/j.jcmgh.2022.09.006. Epub 2022 Sep 20.

Abstract

Background & aims: Signal transducer and activator of transcription 3 (STAT3) is known as a pro-oncogenic transcription factor. Regarding liver carcinogenesis, however, it remains controversial whether activated STAT3 is pro- or anti-tumorigenic. This study aimed to clarify the significance and mechanism of STAT3 activation in hepatocellular carcinoma (HCC).

Methods: Hepatocyte-specific Kras-mutant mice (Alb-Cre KrasLSL-G12D/+; KrasG12D mice) were used as a liver cancer model. Cell lines of hepatoma and stromal cells including stellate cells, macrophages, T cells, and endothelial cells were used for culture. Surgically resected 12 HCCs were used for human analysis.

Results: Tumors in KrasG12D mice showed up-regulation of phosphorylated STAT3 (p-STAT3), together with interleukin (IL)-6 family cytokines, STAT3 target genes, and connective tissue growth factor (CTGF). Hepatocyte-specific STAT3 knockout (Alb-Cre KrasLSL-G12D/+ STAT3fl/fl) downregulated p-STAT3 and CTGF and suppressed tumor progression. In coculture with stromal cells, proliferation, and expression of p-STAT3 and CTGF, were enhanced in hepatoma cells via gp130/STAT3 signaling. Meanwhile, hepatoma cells produced CTGF to stimulate integrin/nuclear factor kappa B signaling and up-regulate IL-6 family cytokines from stromal cells, which could in turn activate gp130/STAT3 signaling in hepatoma cells. In KrasG12D mice, hepatocyte-specific CTGF knockout (Alb-Cre KrasLSL-G12D/+ CTGFfl/fl) downregulated p-STAT3, CTGF, and IL-6 family cytokines, and suppressed tumor progression. In human HCC, single cell RNA sequence showed CTGF and IL-6 family cytokine expression in tumor cells and stromal cells, respectively. CTGF expression was positively correlated with that of IL-6 family cytokines and STAT3 target genes in The Cancer Genome Atlas.

Conclusions: STAT3 is activated by CTGF-mediated tumor-stroma crosstalk to promote HCC progression. STAT3-CTGF positive feedback loop could be a therapeutic target.

Keywords: IL-6 Family Cytokines; Intercellular Interactions; Liver Cancer; Tumor Microenvironment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinogenesis
  • Carcinoma, Hepatocellular* / genetics
  • Connective Tissue Growth Factor* / genetics
  • Connective Tissue Growth Factor* / metabolism
  • Cytokine Receptor gp130 / metabolism
  • Endothelial Cells
  • Humans
  • Interleukin-6 / metabolism
  • Liver Neoplasms* / genetics
  • Mice
  • Proto-Oncogene Proteins p21(ras) / metabolism
  • STAT3 Transcription Factor* / metabolism

Substances

  • Connective Tissue Growth Factor
  • Cytokine Receptor gp130
  • Interleukin-6
  • Proto-Oncogene Proteins p21(ras)
  • STAT3 protein, human
  • STAT3 Transcription Factor
  • CCN2 protein, human