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

Authors Zhao Z, Xiong S, Wang R, Li Y, Wang X, Wang Y, Bai S, Chen W, Zhao Y, Cheng B

Received 26 October 2018

Accepted for publication 19 February 2019

Published 10 April 2019 Volume 2019:11 Pages 2889—2901

DOI https://doi.org/10.2147/CMAR.S192263

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Colin Mak

Peer reviewer comments 4

Editor who approved publication: Dr Chien-Feng Li


Zhenxiong Zhao, Si Xiong, Ronghua Wang, Yawen Li, Xiju Wang, Yun Wang, Shuya Bai, Wei Chen, Yuchong Zhao, Bin Cheng

Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, People’s Republic of China

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.

Keywords: PTFs, HCC, carcinogenesis, metastasis, STAT3 signaling


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