Guidelines For Basic Science
Copyright ©2012 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Jun 14, 2012; 18(22): 2745-2755
Published online Jun 14, 2012. doi: 10.3748/wjg.v18.i22.2745
Interrelationship between microsatellite instability and microRNA in gastrointestinal cancer
Hiroyuki Yamamoto, Yasushi Adachi, Hiroaki Taniguchi, Hiroaki Kunimoto, Katsuhiko Nosho, Hiromu Suzuki, Yasuhisa Shinomura
Hiroyuki Yamamoto, Yasushi Adachi, Hiroaki Kunimoto, Katsuhiko Nosho, Hiromu Suzuki, Yasuhisa Shinomura, First Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan
Hiroaki Taniguchi, Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan
Hiromu Suzuki, Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan
Author contributions: Yamamoto H conceived the topic, reviewed the literature and prepared the manuscript; Adachi Y, Taniguchi H, Kunimoto H, Nosho K and Suzuki H reviewed and analyzed the literature; and Shinomura Y provided intellectual support.
Supported by Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan
Correspondence to: Hiroyuki Yamamoto, MD, FJSIM, PhD, First Department of Internal Medicine, Sapporo Medical University School of Medicine, S1W16 Chuo-ku, Sapporo 060-8543, Japan.
Telephone: +81-11-6112111 Fax: +81-11-6112282
Received: September 28, 2011
Revised: March 2, 2012
Accepted: March 9, 2012
Published online: June 14, 2012

There is an increasing understanding of the roles that microsatellite instability (MSI) plays in Lynch syndrome (by mutations) and sporadic (by mainly epigenetic changes) gastrointestinal (GI) and other cancers. Deficient DNA mismatch repair (MMR) results in the strong mutator phenotype known as MSI, which is the hallmark of cancers arising within Lynch syndrome. MSI is characterized by length alterations within simple repeated sequences called microsatellites. Lynch syndrome occurs primarily because of germline mutations in one of the MMR genes, mainly MLH1 or MSH2, less frequently MSH6, and rarely PMS2. MSI is also observed in about 15% of sporadic colorectal, gastric, and endometrial cancers and in lower frequencies in a minority of other cancers where it is often associated with the hypermethylation of the MLH1 gene. miRNAs are small noncoding RNAs that regulate gene expression at the posttranscriptional level and are critical in many biological processes and cellular pathways. There is accumulating evidence to support the notion that the interrelationship between MSI and miRNA plays a key role in the pathogenesis of GI cancer. As a possible new mechanism underlying MSI, overexpression of miR-155 has been shown to downregulate expression of MLH1, MSH2, and MSH6. Thus, a subset of MSI-positive (MSI+) cancers without known MMR defects may result from miR-155 overexpression. Target genes of frameshift mutation for MSI are involved in various cellular functions, such as DNA repair, cell signaling, and apoptosis. A novel class of target genes that included not only epigenetic modifier genes, such as HDAC2, but also miRNA processing machinery genes, including TARBP2 and XPO5, were found to be mutated in MSI+ GI cancers. Thus, a subset of MSI+ colorectal cancers (CRCs) has been proposed to exhibit a mutated miRNA machinery phenotype. Genetic, epigenetic, and transcriptomic differences exist between MSI+ and MSI− cancers. Molecular signatures of miRNA expression apparently have the potential to distinguish between MSI+ and MSI− CRCs. In this review, we summarize recent advances in the MSI pathogenesis of GI cancer, with the focus on its relationship with miRNA as well as on the potential to use MSI and related alterations as biomarkers and novel therapeutic targets.

Keywords: Microsatellite instability, MicroRNA, DNA mismatch repair, Frameshift mutation, MicroRNA processing