Peri-tumor Fibroblasts Promote Tumorigenesis And Metastasis Of Hepatocellular Carcinoma Via Interleukin6/STAT3 Signaling Pathway

Purpose: Because many hepatocellular carcinoma(HCC)cases develop from fibrotic or cirrhotic livers,fibroblasts are abundant in the microenvironment of HCC.Although the contribution of cancer-associated fibroblasts(CAFs)to the progression of HCC is well established,the role of fibroblasts has not been comprehensively revealed.Patients and methods: The Ray Bio Human Cytokine Antibody Array was used to elucidate the role of peri-tumor fibroblasts(PTFs)in promoting malignant properties of HCC.IL-6 and STAT3 signaling were inhibited in both HCC cell lines and non-tumor L-02 liver cells to further determine its role in the progression of HCC.Moreover,the expression of IL-6 and p Tyr705 STAT3 was detected in HCC samples and peri-tumor liver tissues by immunohistochemical staining.Results: PTFs not only promoted the proliferation,invasion,and metastasis of liver cancer cells,but also stimulated the permanent malignant transformation of human non-tumor L-02 liver cells,resulting in hepatocarcinogenesis in vivo.The Ray Bio Human Cytokine Antibody Array indicated that PTFs secreted a higher level of soluble IL-6 than CAFs.IL-6 derived from PTFs greatly activated STAT3 Tyr705 phosphorylation in both non-tumor L-02 cells and HCC cells.IL-6-neutralizing antibody and STAT3 Tyr705 phosphorylation inhibitor,cryptotanshinone,largely abolished the positive effects of PTFs on HCC carcinogenesis and progression.Moreover,high expression of p Tyr705 STAT3 in peri-tumor tissues was significantly correlated with tumor recurrence rate after three years in a postsurgical follow-up with patients with HCC.Conclusion: These results indicated that PTFs induce carcinogenesis and development of HCC via IL-6 and STAT3 signaling.