Up-regulation of matrix metalloproteinases in a mouse model of chemically induced colitis-associated cancer: the role of microRNAs.

Feiyan Ai,Guiyuan Li,Nan Li,Qiurong Ye,Jian Ma,Xiayu Li,Li Tian,Zailong Qin,Xuemei Zhang,Anliu Tang,Shourong Shen

doi:10.18632/oncotarget.3027

Abstract

Emerging evidence has implicated microRNAs in regulating the production of multiple inflammatory mediators including cytokines and chemokines. We previously elucidated the dynamic activation of key signals that link colitis to colorectal cancer. In this study, we observed a sharp increase in the levels of matrix metalloproteinases (Mmps) that provided a basis for the inflammation-cancer link, and we questioned whether this was a consequence of the dysregulation of Mmp-specific microRNAs, at least partly. We assayed a panel of murine microRNAs that were predicted to target Mmps and found they were downregulated in the inflammation-cancer link. Furthermore, we demonstrated that three murine microRNAs, namely miR-128, -134, and -330, can target the three Mmps Mmp3, Mmp10, and Mmp13, respectively. We also found that the level of the microRNA-processing enzyme Dicer1 was decreased in the inflammation-cancer link. These microRNAs functioned as tumor suppressors in colon cancer cells, attenuating the proliferation, migration, and invasion potential of murine colon cancer cells as well as angiogenesis and the growth of tumors derived from these cells. Our results suggest that microRNAs modulate the production of key inflammatory mediators and that microRNA dysfunction may contribute to the non-resolving inflammation associated with cancer.

Highlights

Inflammation tends to develop when an organism is exposed to a harmful physical or chemical agent(s), infection, or an autoimmune disease
The AOM/dextran sodium sulfate (DSS)-inducible CAC mouse model is a genetically stable and clinically relevant animal model of CAC that closely mimics the pathological course of human ulcerative colitis developing to colorectal tumors [15]
We confirmed those findings, and we observed a dramatic increase in Mmp3, Mmp10, and Mmp13 expression in CAC tissue relative to normal tissue (Figure 1A); their expression was increased in dysplastic tissues and adenocarcinoma tissues and in inflamed tissues

Summary

Introduction

Inflammation tends to develop when an organism is exposed to a harmful physical or chemical agent(s), infection, or an autoimmune disease. A single pretreatment with azoxymethane (AOM) with subsequent repeated ingestion of dextran sodium sulfate (DSS) leads to colon cancer in ~100% of mice [6]. This AOM/DSS-induced CAC mouse model www.impactjournals.com/oncotarget simulates the histological changes of the colon observed in CAC patients. With this model, we discovered that different key signaling pathways [NF-κB, STAT3, p38 mitogen-activated protein kinase (MAPK), and Wnt/βcatenin] and their target genes are hyperactivated in different phases of inflammation-associated cancer [7]. Among the genes activated by these signaling pathways, the dramatic upregulation of those genes encoding matrix metalloproteinases (Mmps) attracted our attention

Methods

Results

Conclusion