Novel STAT binding elements mediate IL-6 regulation of MMP-1 and MMP-3

Samuel J. Cutler; James D. Doecke; Ibtisam Ghazawi; Jinbo Yang; Lyn R. Griffiths; Kevin J. Spring; Stephen J. Ralph; Albert S. Mellick

doi:10.1038/s41598-017-08581-y

Novel STAT binding elements mediate IL-6 regulation of MMP-1 and MMP-3

Samuel J. Cutler, James D. Doecke, Ibtisam Ghazawi, Jinbo Yang, Lyn R. Griffiths, Kevin J. Spring, Stephen J. Ralph, Albert S. Mellick

Western Sydney University

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

Abstract

Dynamic remodelling of the extracellular matrix (ECM) is a key feature of cancer progression. Enzymes that modify the ECM, such as matrix metalloproteinases (MMPs), have long been recognised as important targets of anticancer therapy. Inflammatory cytokines are known to play a key role in regulating protease expression in cancer. Here we describe the identification of gamma-activated site (GAS)-like, signal transducer and activator of transcription (STAT) binding elements (SBEs) within the proximal promoters of the MMP-1 and MMP-3 genes, which in association with AP-1 components (c-Fos or Jun), bind STAT-1 in a homodimer like complex (HDLC). We further demonstrate that MMP expression and binding of this complex to SBEs can either be enhanced by interleukin (IL)-6, or reduced by interferon gamma (IFN-γ), and that IL-6 regulation of MMPs is not STAT-3 dependent. Collectively, this data adds to existing understanding of the mechanism underlying cytokine regulation of MMP expression via STAT-1, and increases our understanding of the links between inflammation and malignancy in colon cancer.

Original language	English
Article number	8526
Number of pages	12
Journal	Scientific Reports
Volume	7
Issue number	1
DOIs	https://doi.org/10.1038/s41598-017-08581-y
Publication status	Published - 2017

Open Access - Access Right Statement

Â© The Author(s) 2017. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Keywords

cancer
colon (anatomy)
extracellular matrix
inflammation
metalloproteinases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41598-017-08581-y

Cite this

@article{372c6d373cac442998b5e46856fcd81f,

title = "Novel STAT binding elements mediate IL-6 regulation of MMP-1 and MMP-3",

abstract = "Dynamic remodelling of the extracellular matrix (ECM) is a key feature of cancer progression. Enzymes that modify the ECM, such as matrix metalloproteinases (MMPs), have long been recognised as important targets of anticancer therapy. Inflammatory cytokines are known to play a key role in regulating protease expression in cancer. Here we describe the identification of gamma-activated site (GAS)-like, signal transducer and activator of transcription (STAT) binding elements (SBEs) within the proximal promoters of the MMP-1 and MMP-3 genes, which in association with AP-1 components (c-Fos or Jun), bind STAT-1 in a homodimer like complex (HDLC). We further demonstrate that MMP expression and binding of this complex to SBEs can either be enhanced by interleukin (IL)-6, or reduced by interferon gamma (IFN-γ), and that IL-6 regulation of MMPs is not STAT-3 dependent. Collectively, this data adds to existing understanding of the mechanism underlying cytokine regulation of MMP expression via STAT-1, and increases our understanding of the links between inflammation and malignancy in colon cancer.",

keywords = "cancer, colon (anatomy), extracellular matrix, inflammation, metalloproteinases",

author = "Cutler, {Samuel J.} and Doecke, {James D.} and Ibtisam Ghazawi and Jinbo Yang and Griffiths, {Lyn R.} and Spring, {Kevin J.} and Ralph, {Stephen J.} and Mellick, {Albert S.}",

year = "2017",

doi = "10.1038/s41598-017-08581-y",

language = "English",

volume = "7",

journal = "Scientific Reports",

issn = "2045-2322",

publisher = "Nature Publishing Group",

number = "1",

}

TY - JOUR

T1 - Novel STAT binding elements mediate IL-6 regulation of MMP-1 and MMP-3

AU - Cutler, Samuel J.

AU - Doecke, James D.

AU - Ghazawi, Ibtisam

AU - Yang, Jinbo

AU - Griffiths, Lyn R.

AU - Spring, Kevin J.

AU - Ralph, Stephen J.

AU - Mellick, Albert S.

PY - 2017

Y1 - 2017

N2 - Dynamic remodelling of the extracellular matrix (ECM) is a key feature of cancer progression. Enzymes that modify the ECM, such as matrix metalloproteinases (MMPs), have long been recognised as important targets of anticancer therapy. Inflammatory cytokines are known to play a key role in regulating protease expression in cancer. Here we describe the identification of gamma-activated site (GAS)-like, signal transducer and activator of transcription (STAT) binding elements (SBEs) within the proximal promoters of the MMP-1 and MMP-3 genes, which in association with AP-1 components (c-Fos or Jun), bind STAT-1 in a homodimer like complex (HDLC). We further demonstrate that MMP expression and binding of this complex to SBEs can either be enhanced by interleukin (IL)-6, or reduced by interferon gamma (IFN-γ), and that IL-6 regulation of MMPs is not STAT-3 dependent. Collectively, this data adds to existing understanding of the mechanism underlying cytokine regulation of MMP expression via STAT-1, and increases our understanding of the links between inflammation and malignancy in colon cancer.

AB - Dynamic remodelling of the extracellular matrix (ECM) is a key feature of cancer progression. Enzymes that modify the ECM, such as matrix metalloproteinases (MMPs), have long been recognised as important targets of anticancer therapy. Inflammatory cytokines are known to play a key role in regulating protease expression in cancer. Here we describe the identification of gamma-activated site (GAS)-like, signal transducer and activator of transcription (STAT) binding elements (SBEs) within the proximal promoters of the MMP-1 and MMP-3 genes, which in association with AP-1 components (c-Fos or Jun), bind STAT-1 in a homodimer like complex (HDLC). We further demonstrate that MMP expression and binding of this complex to SBEs can either be enhanced by interleukin (IL)-6, or reduced by interferon gamma (IFN-γ), and that IL-6 regulation of MMPs is not STAT-3 dependent. Collectively, this data adds to existing understanding of the mechanism underlying cytokine regulation of MMP expression via STAT-1, and increases our understanding of the links between inflammation and malignancy in colon cancer.

KW - cancer

KW - colon (anatomy)

KW - extracellular matrix

KW - inflammation

KW - metalloproteinases

UR - http://handle.westernsydney.edu.au:8081/1959.7/uws:43720

U2 - 10.1038/s41598-017-08581-y

DO - 10.1038/s41598-017-08581-y

M3 - Article

SN - 2045-2322

VL - 7

JO - Scientific Reports

JF - Scientific Reports

IS - 1

M1 - 8526

ER -

Novel STAT binding elements mediate IL-6 regulation of MMP-1 and MMP-3

Abstract

Open Access - Access Right Statement

Keywords

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this