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STAT3 is activated by CTGF-mediated tumor-stroma cross talk to promote HCC progression.

Open AccessPublished:September 19, 2022DOI:https://doi.org/10.1016/j.jcmgh.2022.09.006
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      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 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/NF-kB 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.

      Graphical abstract

      Keywords

      Abbreviations:

      DEN (diethylnitrosamine), DMEM (Dulbecco's modified Eagle’s medium), CNTF (ciliary neurotrophic factor), CTF-1 (cardiotrophin-1), CTGF (connective tissue growth factor), HCC (hepatocellular carcinoma), HPF (high-power field), HSC (hepatic stellate cell), IRB (institutional Review Board), JAK (Janus kinase), JCRB/HSRRB (Japanese Collection of Research Bioresources/Health Science Research Resources Bank), LIF (leukemia inhibitory factor, NOD/Shi-scid/IL-2Rγ (null) (NOG)), OSM (oncostatin M), PCNA (proliferating cell nuclear antigen), PMA (phorbol 12-myristate 13-acetate), scRNA-seq (single-cell RNA sequencing), shRNA (short hairpin RNA), STAT3 (signal transducer and activator of transcription 3), TCGA (The Cancer Genome Atlas), UMAP (uniform manifold approximation and projection)