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

Abstract

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 G(0)/G(1) 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.

Biological and Clinical Relevance of miRNA Expression Signatures in Primary Plasma Cell Leukemia

“…Specific CN/ miRNA expression correlations found in the present series of pPCLs were previously identified by us in patients with multiple myeloma and/or human myeloma cell lines, that is, miR-342-3p, miR-22, miR-19a, miR-20a, miR-20a à , miR-140-5p, miR-210, miR-15a, miR-30e, and miR-30e à (16,21). In particular, several of the identified downregulated miRNAs in association with the loss of the corresponding genomic loci have already been linked to cancer as having a tumor suppressor role: this is the case of miR-22 (22,23), miR-30e and miR-30c (24), miR-331-3p (25), and miR-342-3p (26). The downregulation of miR-15a in patients carrying chromosome 13 deletion is of particular importance given the frequency of this genomic lesion in pPCL and the experimental evidence that it may act as a tumor suppressor in malignant plasma cells (27,28).…”

RASSF tumor suppressor gene family: Biological functions and regulation

“…We can speculate that microRNA targeting DNMTs or other proteins involved in epigenetic regulation may also affect RASSF1A expression. One study revealed that overexpressed DNMT1 in colorectal cancer tissues and cell lines was associated with downregulated miR-342 [161]. Restoration of miR-342 resulted in a dramatic reduction of the expression of DNMT1 and this in turn reactivated RASSF1A along with ADAM23, Hint1 and RECKS genes via promoter demethylation.…”

Overexpression of Sirt7 Exhibits Oncogenic Property and Serves as a Prognostic Factor in Colorectal Cancer

“…Despite the innovative therapeutic strategies applied in colorectal cancer, the prognosis has not significantly changed in the last 20 years. In past decades, studies have reported alternative factors involved in colorectal cancer pathogenesis, including genetic mutations in certain oncogenes or tumor suppressor genes (KRAS, APC, DCC, Smad-2, and Smad-4) and changes in the p53, b-catenin, TGF-b, and WNT transduction pathways (2,3). These findings suggest that colorectal carcinogenesis results from an accumulation of genetic alterations.…”