Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer

Xueqing Sun,Ying Wang,Yimin Lao,Jie Yang,Huiqin Zhu,Qing Qu,Mi Zhang,Jing Yi,Xiaoling Yin,Mingang Hao

doi:10.1186/s12885-019-6333-6

Abstract

sBackgroundInterleukin-6 (IL-6) is commonly highly secreted in the breast cancer (BrCA) microenvironment and implicated in disease development. In this study, we aimed to determine the role of the IL-6/pSTAT3/HIC1 axis in the breast cancer microenvironment, including in cancer-associated fibroblasts (CAFs) and breast cancer cells.MethodsStromal fibroblasts from the breast cancer tissue were isolated, and the supernatants of the fibroblasts were analyzed. Recombinant human IL-6 (rhIL-6) was applied to simulate the effect of CAF-derived IL-6 to study the mechanism of HIC1 (tumor suppressor hypermethylated in cancer 1) downregulation. IL-6 was knocked down in the high IL-6-expressing BrCA cell line MDA-MB-231, which enabled the investigation of the IL-6/pSTAT3/HIC1 axis in the autocrine pathway.ResultsIncreased IL-6 was found in the supernatant of isolated CAFs, which suppressed HIC1 expression in cancer cells and promoted BrCA cell proliferation. After stimulating the BrCA cell line SK-BR-3 (where IL-6R is highly expressed) with rhIL-6, signal transducers and activators of transcription 3 (STAT3) was found to be phosphorylated and HIC1 decreased, and a STAT3 inhibitor completely rescued HIC1 expression. Moreover, HIC1 was restored upon knocking down IL-6 expression in MDA-MB-231 cells, accompanied by a decrease in STAT3 activity.ConclusionsThese findings indicate that IL-6 downregulates the tumor suppressor HIC1 and promotes BrCA development in the tumor microenvironment through paracrine or autocrine signaling.

Highlights

Interleukin-6 (IL-6) is commonly highly secreted in the breast cancer (BrCA) microenvironment and implicated in disease development
Increased IL-6 was found in the supernatant of isolated cancer-associated fibroblasts (CAFs), which suppressed Tumor suppressor hypermethylated in cancer 1 (HIC1) expression in cancer cells and promoted BrCA cell proliferation
HIC1 was restored upon knocking down IL-6 expression in MDA-MB-231 cells, accompanied by a decrease in signal transducers and activators of transcription 3 (STAT3) activity

Summary

Introduction

Interleukin-6 (IL-6) is commonly highly secreted in the breast cancer (BrCA) microenvironment and implicated in disease development. Cancer-associated fibroblasts (CAFs) are the most abundant cell types in the tumor microenvironment; they secrete various cytokines, such as CXCL12, IL-1, IL-8, IL-10, IL-6, TNF-α and MCP-l, through the paracrine pathway to act on tumor. IL-6 trans-signaling can occur in any cell with membrane-bound gp130 and involves IL-6 binding to sIL-6R to activate signaling through membranebound gp130. The classical signaling pathways that bind to receptors through the membrane are primarily regenerative and protective; in contrast to the classical pathway, the trans-signaling pathway of sIL-6R promotes inflammation [13]. In the intracellular signaling phase of the trans-signaling pathway [13], a family of tyrosine kinases known as Janus kinases (JAK) is activated after IL-6 binds to the receptor complex. JAK phosphorylates the tyrosine residues in the cytoplasmic region of gp130, which recruits STAT transcription factors that subsequently activate a series of signals that coordinate MAPK and PI3K activation, thereby activating PI3K/Akt/NF-κB for anti-apoptotic and pro-proliferation effects [13, 14]

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