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Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer
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 fibroblast...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891969/ https://www.ncbi.nlm.nih.gov/pubmed/31795965 http://dx.doi.org/10.1186/s12885-019-6333-6 |
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author | Sun, Xueqing Qu, Qing Lao, Yimin Zhang, Mi Yin, Xiaoling Zhu, Huiqin Wang, Ying Yang, Jie Yi, Jing Hao, Mingang |
author_facet | Sun, Xueqing Qu, Qing Lao, Yimin Zhang, Mi Yin, Xiaoling Zhu, Huiqin Wang, Ying Yang, Jie Yi, Jing Hao, Mingang |
author_sort | Sun, Xueqing |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6891969 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-68919692019-12-11 Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer Sun, Xueqing Qu, Qing Lao, Yimin Zhang, Mi Yin, Xiaoling Zhu, Huiqin Wang, Ying Yang, Jie Yi, Jing Hao, Mingang BMC Cancer Research Article 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. BioMed Central 2019-12-03 /pmc/articles/PMC6891969/ /pubmed/31795965 http://dx.doi.org/10.1186/s12885-019-6333-6 Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Sun, Xueqing Qu, Qing Lao, Yimin Zhang, Mi Yin, Xiaoling Zhu, Huiqin Wang, Ying Yang, Jie Yi, Jing Hao, Mingang Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer |
title | Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer |
title_full | Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer |
title_fullStr | Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer |
title_full_unstemmed | Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer |
title_short | Tumor suppressor HIC1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the IL-6/pSTAT3 axis in breast cancer |
title_sort | tumor suppressor hic1 is synergistically compromised by cancer-associated fibroblasts and tumor cells through the il-6/pstat3 axis in breast cancer |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891969/ https://www.ncbi.nlm.nih.gov/pubmed/31795965 http://dx.doi.org/10.1186/s12885-019-6333-6 |
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