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.
Highlights
The cancer microenvironment is made up of many host derived non-tumor cells that play an important role in driving cancer progression by mediating processes as diverse as angiogenesis[1, 2], fibrosis[3], and metastatic spread[4]
These include, Collagenase I (MMP-1), which is proposed to be regulated by Oncostatin M (OSM) via signal transducer and activator of transcription (STAT)-3 binding to an STAT binding elements (SBEs) located in a region of the human gene promoter proximal to the start site of transcription[24, 25], as well as matrix metalloproteinases (MMPs)-3 (Stromelysin), which appears to be regulated by IL-6 via a distal SBE26, 27
We present data showing that IL-6 regulates MMP expression via proximal gamma-activated site (GAS)-like SBEs, and that IL-6 treatment leads to binding of a novel complex, which contains both STAT-1 and components of activated protein (AP)-1, but not STAT-3
Summary
The cancer microenvironment is made up of many host derived non-tumor cells that play an important role in driving cancer progression by mediating processes as diverse as angiogenesis[1, 2], fibrosis[3], and metastatic spread[4]. DNA binding sites for STATs in the promoters of genes induced by type I IFN10, type II IFN and interleukin (IL)-6 were further confirmed by electrophoretic mobility shift assays (EMSA)[11] and mutational analysis[12] In this way, the type I IFN-activated complex (ISGF3) was found to recognise a direct repeat consensus sequence GAAANNGAAANN, referred to as the IFN-stimulated response element (ISRE), and the type II IFN-γ activated complex (aka γ-activated factor) was shown to recognise the sequence TT(C/A) CNN(G/T)AA, referred to as the IFN-γ-activated sequence (GAS). This finding provides a novel insight into inflammatory cytokine signaling and represents an important consideration for the development of anti-cancer drugs targeting STAT-mediated cytokine signaling[31]
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