<p>Peri-tumor fibroblasts promote tumorigenesis and metastasis of hepatocellular carcinoma via Interleukin6/STAT3 signaling pathway</p>

Abstract

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 RayBio 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 pTyr705 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 RayBio 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 pTyr705 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.

Curcumin suppresses the proliferation and tumorigenicity of Cal27 by modulating cancer‐associated fibroblasts of TSCC

“…In the present study, the Western blot analysis showed that although higher in CAFs, the levels of α-SMA and pSMAD2/3 were also very high in PTFs. A recent study reveals that PTFs induce carcinogenesis and development of hepatocellular carcinoma via IL-6 and STAT3 signaling (Zhao et al, 2019). This suggests that resident fibroblasts from peri-tumor tissue clinically considered to be normal have perhaps had partial transdifferentiation.…”

JAK/STAT signaling in hepatocellular carcinoma

“…Consequently, this inhibited lung metastasis formation and significantly prolonged survival time [36]. Zhao et al also demonstrated that inhibition of STAT3 phosphorylation by CTS successfully impeded the invasion of HCC cells which was induced by peri-tumor fibroblasts [60]. Besides, STAT3 can also induce the invasiveness of HCC tumors by upregulating the expression of epithelial-mesenchymal transition proteins such as Slug and Twist [61,62].…”

Heterogeneity of cancer-associated fibroblasts and roles in the progression, prognosis, and therapy of hepatocellular carcinoma

“…Fibroblasts that affect HCC progression are not only restricted to CAFs in HCC tumor tissues, peritumor fibroblasts (PTFs), and fibroblasts at the site of metastasis but also have an effect on HCC progression. Zhao et al found that PTFs promote the proliferation, migration, and invasion of HCC cells more than CAFs do, and this promotion may be mediated by increased levels of IL-6 and activation of IL-6/STAT3 signaling [59]. Jiang et al also showed that PTFs promote in vitro migration and invasion of HCC cells and their in vivo tumorigenesis and metastasis [60].…”