Cellular and Molecular Gastroenterology and Hepatology (Jan 2023)

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

  • Yuki Makino,
  • Hayato Hikita,
  • Seiya Kato,
  • Masaya Sugiyama,
  • Minoru Shigekawa,
  • Tatsuya Sakamoto,
  • Yoichi Sasaki,
  • Kazuhiro Murai,
  • Sadatsugu Sakane,
  • Takahiro Kodama,
  • Ryotaro Sakamori,
  • Shogo Kobayashi,
  • Hidetoshi Eguchi,
  • Nobuyuki Takemura,
  • Norihiro Kokudo,
  • Hideki Yokoi,
  • Masashi Mukoyama,
  • Tomohide Tatsumi,
  • Tetsuo Takehara

Journal volume & issue
Vol. 15, no. 1
pp. 99 – 119

Abstract

Read online

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