Cancer-associated fibroblasts promote the progression and chemoresistance of HCC by inducing IGF-1.

Autor: Lv KJ; Phase I clinical trial research ward, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China., Yu SZ; Department of Thoracic Medical Oncology, Zhejiang Cancer Hospital, Hangzhou, Zhejiang, PR China., Wang Y; Department of Respiratory and Critical Care Medicine, The Second Affiliated Hospital of Xian Jiaotong University, China., Zhang SR; Department of Medical Oncology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China., Li WY; Department of Medical Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China., Hou J; Department of Pathology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China., Tan DL; Phase I clinical trial research ward, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China., Guo H; Phase I clinical trial research ward, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China; Department of Medical Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China. Electronic address: guohuihappy97@163.com., Hou YZ; Department of Medical Oncology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, PR China; Department of Pathogenic Microbiology and Immunology, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, ShaanXi 710061, China. Electronic address: houyuzhu@xjtu.edu.cn.
Jazyk: angličtina
Zdroj: Cellular signalling [Cell Signal] 2024 Dec; Vol. 124, pp. 111378. Date of Electronic Publication: 2024 Sep 04.
DOI: 10.1016/j.cellsig.2024.111378
Abstrakt: Crosstalk between cancer-associated fibroblasts (CAFs) and tumour cells plays a critical role in multiple cancers, including hepatocellular carcinoma (HCC). CAFs contribute to tumorigenesis by secreting growth factors, modifying the extracellular matrix, supporting angiogenesis, and suppressing antitumor immune responses. However, effect and mechanism of CAF-mediated promotion of hepatocellular carcinoma cells are still unclear. In study, we demonstrated CAFs promoted the proliferation and inhibited the apoptosis of HCC cells by secreting interleukin-6 (IL-6), which induced autocrine insulin-like growth factor-1 (IGF-1) in HCC. IGF-1 promoted the progression and chemoresistance of HCC. IGF-1 receptor (IGF-1R) inhibitor NT157 abrogated the effect of CAF-derived IL-6 and autocrine IGF-1 on HCC. Mechanistic studies revealed that NT157 decreased IL-6-induced IGF-1 expression by inhibiting STAT3 phosphorylation and led to IRS-1 degradation, which mediated the proliferation of tumour by activating AKT signalling in ERK-dependent manner. Inhibition of IGF-1R also enhanced the therapeutic effect of sorafenib on HCC, especially chemoresistant tumours. STATEMENT OF SIGNIFICANCE: Our study showed IL-6-IGF-1 axis played crucial roles in the crosstalk between HCC and CAFs, providing NT157 inhibited of STAT3 and IGF-1R as a new targeted therapy in combination with sorafenib.
Competing Interests: Declaration of competing interest The authors declare no potential conflicts of interest.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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