MicroRNA-342 inhibits colorectal cancer cell proliferation and invasion by directly targeting DNA methyltransferase 1

• Published in: Carcinogenesis (New York) Vol. 32; no. 7; pp. 1033 - 1042
• Main Authors: Wang, Hui, Wu, Jiangxue, Meng, Xiangqi, Ying, Xiaofang, Zuo, Yufang, Liu, Ranyi, Pan, Zhizhong, Kang, Tiebang, Huang, Wenlin
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.07.2011
• Subjects: Animals; Biological and medical sciences; Carcinogenesis, carcinogens and anticarcinogens; Cell Line, Tumor; Cell Proliferation; Colorectal Neoplasms - enzymology; Colorectal Neoplasms - pathology; Colorectal Neoplasms - physiopathology; DNA (Cytosine-5-)-Methyltransferase 1; DNA (Cytosine-5-)-Methyltransferases - metabolism; DNA Methylation; G1 Phase; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Male; Medical sciences; Mice; Mice, Nude; MicroRNAs - metabolism; MicroRNAs - physiology; Neoplasm Invasiveness; Neoplasm Metastasis; Oligonucleotides; Oncogenes; Promoter Regions, Genetic; Resting Phase, Cell Cycle; Reverse Transcriptase Polymerase Chain Reaction; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Cell proliferation; Rectal disease; RNA interference; Targeting; Colorectal cancer; Micro RNA; Malignant tumor; Metastasis; Invasion; Colonic disease; Gene silencing; Target; Digestive diseases; Intestinal disease; Inhibitor; Tumor cell; Cancer
• ISSN: 0143-3334; 1460-2180
• DOI: 10.1093/carcin/bgr081

Overexpressed DNA methyltransferase 1 (DNMT1) strongly contributes to tumor suppressor gene silencing in colorectal cancer (CRC). However, the underlying mechanism of DNMT1 overexpression is still unclear. MicroRNAs (miRNA) have been implicated as gene regulators controlling diverse biological processes, including carcinogenesis. In this study, we investigated whether some miRNA is involved in the regulation of DNMT1 and thus play a functional role in CRC. Our results showed that miR-342 was downregulated in CRC tissues and cell lines. Restoration of miR-342 resulted in a dramatic reduction of the expression of DNMT1 at both messenger RNA and protein levels by directly targeting its 3′ untranslated region. This in turn reactivated ADAM23, Hint1, RASSF1A and RECK genes via promoter demethylation. Furthermore, the enhanced expression of miR-342 could significantly inhibit SW480 cell proliferation in vitro (P = 0.006). Further investigation demonstrated G0/G1 cell cycle arrest in SW480 cells, which was associated with an upregulation of p21 and downregulation of cyclinE and CDK2. Overexpression of miR-342 also inhibited SW480 cell invasion. The in vivo antitumor effect was evaluated in SW480 cells with lentivirus-mediated expression of miR-342. Results showed that overexpression of miR-342 significantly inhibited tumor growth and lung metastasis in nude mice (P = 0.034). Our findings describe a new mechanism for the regulation of DNMT1 and aberrant DNA hypermethylation in CRC. This is also the first report to demonstrate that miR-342 may act as a tumor suppressor gene in CRC development. The newly identified miR-342/DNMT1 link provides a new, potential therapeutic target for the treatment of CRC.