Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer
Xueqing Sun,
Qing Qu,
Yimin Lao,
Mi Zhang,
Xiaoling Yin,
Huiqin Zhu,
Ying Wang,
Jie Yang,
Jing Yi,
Mingang Hao
Affiliations
Xueqing Sun
Department of Biochemistry and Molecular Cell Biology, Shanghai key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Qing Qu
Department of Oncology, Shanghai Jiao Tong University School of Medicine, Ruijin Hospital
Yimin Lao
Department of Biochemistry and Molecular Cell Biology, Shanghai key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Mi Zhang
Institution of Life Science, Chongqing Medical University
Xiaoling Yin
Department of Otolaryngology Head and Neck Surgery, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine
Huiqin Zhu
Department of Biochemistry and Molecular Cell Biology, Shanghai key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Ying Wang
Department of Biochemistry and Molecular Cell Biology, Shanghai key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Jie Yang
Department of Biochemistry and Molecular Cell Biology, Shanghai key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Jing Yi
Department of Biochemistry and Molecular Cell Biology, Shanghai key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Mingang Hao
Department of Biochemistry and Molecular Cell Biology, Shanghai key Laboratory of Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine
Abstracts Background Interleukin-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. Methods Stromal 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. Results Increased 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. Conclusions These findings indicate that IL-6 downregulates the tumor suppressor HIC1 and promotes BrCA development in the tumor microenvironment through paracrine or autocrine signaling.
