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

Abstract

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. 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. • In the coculture system, CAFs derived IL-6, which can promote the progression of HCC by inducing autocrine IGF-1 in HCC. • NT157 enhanced the activation of the ERKMAPK pathway and blocked IGF-1/IRS1/AKT signalling by IRS1/2. • CAFs led to the resistance of HCC to sorafenib through IL-6 and IGF-1. • Synergy of CAFs was seen between NT157 and sorafenib in the treatment of HCC, most likely due to p-ERK inhibition. • NT157 may be a potential drug for reversing sorafenib resistance by inhibiting IGF1R/AKT signalling in HCC.

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