Epigenetic silencing of miR-520c leads to induced S100A4 expression and its mediated colorectal cancer progression

Abstract

The S100 calcium-binding protein A4 (S100A4) induces epithelial mesenchymal transition, migration, invasion, angiogenesis and metastasis. Its induced expression in several cancer types correlates with poor prognosis. Apart from the functional and transcriptional regulatory aspects of S100A4, its post-transcriptional regulation is not yet clearly elucidated. In this study, we show that microRNAs (miR) miR-505-5p and miR-520c-3p target the 3′-UTR of S100A4 and inhibits its expression and its mediated migration and invasion. 5-Aza treatment significantly increased miR-520c-3p expression and reduced the S100A4 protein amounts. The upstream promoter region of miR-520c is hypermethylated irrespective of the metastasis status of colorectal cancer (CRC) patient tissues and in all analyzed CRC cell lines. Moreover, in a cohort of CRC patient specimen (n = 59), miR-520c-3p was significantly downregulated. miR-520c-3p stably expressing HCT116 cells showed a reduced metastasis formation in livers after implanting in mice spleen. Taken together, our findings demonstrate that S100A4 is post-transcriptionally regulated by tumor suppressor miRs, miR-505c-5p and miR-520c-3p, and particularly miR-520c-3p expression is epigenetically silenced in CRC.

MicroRNA‐520c‐3p functions as a novel tumor suppressor in lung adenocarcinoma

“…The epigenetic regulation of genes is widely involved in cancer development . Previous studies have reported that canonical DNA methylation induced a low expression of miRNAs in various kinds of cancers . Our results indicate that such a mechanism also exists in the downregulation of miR‐520c‐3p in LUAD.…”

“…A few previous studies reported that microRNA‐520c‐3p (miR‐520c‐3p) plays important roles in several kinds of malignant diseases, including lymphoma , breast cancer , fibrosarcoma , hepatocellular carcinoma (HCC) , colorectal cancer (CRC) , glioma , prostate cancer , and gastric cancer . Of these studies, some indicated that miR‐520c‐3p facilitates tumor growth .…”

“…A few previous studies reported that microRNA-520c-3p (miR-520c-3p) plays important roles in Abbreviations 5-aza-dC, 5-aza-2 0 -deoxy-citydine; BrdU, Bromodeoxyuridine; BSP, bisulfite sequencing PCR; CCK8, cell counting kit 8; CRC, colorectal cancer; edgeR, differential expression analysis of digital gene expression data; FDR, false discovery rates; F, forward; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GEO, Gene Expression Omnibus; GSEA, Gene Set Enrichment Analysis; HCC, hepatocellular carcinoma; HRP, horseradish peroxidase; IHC, immunohistochemistry; Limma, linear models for microarray and RNA-seq data; LN, lymph node; LUAD, lung adenocarcinoma; miR-520c-3p, microRNA-520c-3p; miRNA-seq, miRNA sequencing; mt, mutant; NC, negative control; NSCLC, non-small cell lung cancer; OS, overall survival; qRT-PCR, quantitative reverse transcription polymerase chain reaction; RNA-seq, RNA sequencing; R, reverse; SD, standard deviation; TCGA, The Cancer Genome Atlas; TSS, transcription start site; wt, wild-type; YY1, Yin Yang 1. several kinds of malignant diseases, including lymphoma [8], breast cancer [7,9], fibrosarcoma [10], hepatocellular carcinoma (HCC) [11][12][13], colorectal cancer (CRC) [14], glioma [15], prostate cancer [16], and gastric cancer [17]. Of these studies, some indicated that miR-520c-3p facilitates tumor growth [9,10,16,17].…”

“…Of these studies, some indicated that miR-520c-3p facilitates tumor growth [9,10,16,17]. In contrast, in some kinds of malignant diseases, miR-520c-3p functions as a tumor suppressor [7,8,[11][12][13][14][15]. Lung cancer is a malignant disease with one of the highest incidence rates, and it is the leading cause of cancer-related death worldwide [18].…”

HOXA-AS2 Promotes Proliferation and Induces Epithelial-Mesenchymal Transition via the miR-520c-3p/GPC3 Axis in Hepatocellular Carcinoma

“…Recent study has demonstrated that miR-520c-3p negatively regulates epithelial-mesenchymal transition (EMT) by targeting IL-8 to suppress the invasion and migration of breast cancer [16]. In addition, miR-520c-3p could target the 3'-UTR of S100A4 and inhibits its expression and its mediated migration and invasion of colorectal cancer [17].…”