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MACC1 is post-transcriptionally regulated by miR-218 in colorectal cancer

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Item Type:Article
Title:MACC1 is post-transcriptionally regulated by miR-218 in colorectal cancer
Creators Name:Ilm, K. and Fuchs, S. and Mudduluru, G. and Stein, U.
Abstract:Metastasis is a multistep molecular network process, which is lethal for more than 90% of the cancer patients. Understanding the regulatory functions of metastasis-inducing molecules is in high demand for improved therapeutic cancer approaches. Thus, we studied the post-transcriptional regulation of the crucial carcinogenic and metastasis-mediating molecule metastasis associated in colon cancer 1 (MACC1). In silico analysis revealed MACC1 as a potential target of miR-218, a tumor suppressor miRNA. Expression of these two molecules inversely correlated in colorectal cancer (CRC) cell lines. In a cohort of CRC patient tissues (n = 59), miR-218 is significantly downregulated and MACC1 is upregulated compared with normal mucosa. Luciferase reporter assays with a construct of the MACC1-3'-UTR harboring either the wild type or the mutated miR-218 seed sequence confirmed the specificity of the targeting. miR-218 inhibited significantly MACC1 protein expression, and consistently, MACC1-mediated migration, invasion and colony formation in CRC cells. Anti-miR-218 enhanced the MACC1-mediated migration, invasion and colony formation. Similar findings were observed in the gastric cancer cell line MKN-45. Further, we performed methylation-specific PCR of the SLIT2 and SLIT3 promoter, where miR-218 is encoded in intronic regions. The SLIT2 and SLIT3 promoters are hypermethylated in CRC cell lines. miR-218 and SLIT2 expressions correlated positively. Methyltransferase inhibitor 5-Azacytidine induced miR-218 expression and inhibited the expression of its target MACC1. We also determined that MACC1 has alternative polyadenylation (APA) sites, which results in different lengths of 3'-UTR variants in a CRC cell line. Taken together, miR-218 is post-transcriptionally inhibiting the MACC1 expression and its metastasis-inducing abilities.
Keywords:Colorectal Cancer, MACC1, miR-218, Epigenetic Regulation, Alternative Polyadenylation
Publisher:Impact Journals (U.S.A.)
Page Range:53443-53458
Date:16 August 2016
Official Publication:https://doi.org/10.18632/oncotarget.10803
PubMed:View item in PubMed

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