Methylation of an intronic region regulates miR-199a in testicular tumor malignancy

Abstract

In the testicular cancer cell line, NT2, we previously demonstrated that differentially methylated regions were located in introns or intergenic regions, and postulated these might regulate non-coding RNAs. Three micro-RNAs and three small nucleolar RNAs were differentially methylated; one, miR-199a, was associated with the progression and prognosis of gastric and ovarian cancers. In this report we document, by epigenomic profiling of testicular tissue, that miR-199a is transcribed as antisense of dynamin 3 (chromosome 1q24.3), and hypermethylation of this region is correlated with miR-199a-5p/3p repression and tumor malignancy. Re-expression of miR-199a in testicular cancer cells led to suppression of cell growth, cancer migration, invasion and metastasis. The miR-199a-5p, one of two mature miRNA species derived from miR-199a, is associated with tumor malignancy. We further identified the embryonal carcinoma antigen podocalyxin-like protein 1 (PODXL), an anti-adhesive protein expressed in aggressive tumors, as a target of miR-199a-5p. We demonstrated PODXL is overexpressed in malignant testicular tumor, and cellular depletion of PODXL resulted in suppression of cancer invasion. The inverse relationship between PODXL and miR-199a-5p expression suggests PODXL is a downstream effector mediating the action of miR199a-5p. This report identifies DNA methylation, miR-199a dysregulation and PODXL as critical factors in tumor malignancy.

The MicroRNA miR-199a-5p Down-regulation Switches on Wound Angiogenesis by Derepressing the v-ets Erythroblastosis Virus E26 Oncogene Homolog 1-Matrix Metalloproteinase-1 Pathway

“…miR-107, a miR down-regulated by hypoxia, attenuates cell migration (37,38) and blocks VEGF-dependent angiogenesis by targeting hypoxia-inducing factor (HIF)-1␤ (39). The current study, together with findings from previous reports, reinforces the concept that miR-199a-5p not only inhibits cell migration (9,13,16) but also exerts potent angiostatic effect on endothelial cells by targeting a discrete subset of gene(s).…”

“…It is expressed in a variety of organs including the brain (6), liver (9), stomach (10), ovarian tissue (11,12), testicular tissue (13), and the cardiovascular system, such as in cardiomyocytes (7,8) and endothelial cells (14,15). Recent evidence revealed that miR-199a-5p plays a critical role in attenuating cell migration and in limiting cancer cell metastasis by targeting receptor tyrosine kinase Discoidin domain receptor-1 (9), Axl (16), and anti-adhesive transmembrane glycoprotein podocalyxin-like protein 1 (13). We hypothesized that miR-199a-5p exerts angiostatic effects on endothelial cells.…”

MicroRNA-199a is induced in dystrophic muscle and affects WNT signaling, cell proliferation, and myogenic differentiation

“…12,21,40 Another recent study showed that miR-199a-5p expression was upregulated in mice with idiopathic pulmonary fibrosis (IPF), suggesting that miR-199a-5p could regulate tissue fibrosis in different types of fibroproliferative diseases. 41 MiR-199a-5p can also regulate cardiomyocyte size during cardiac hypertrophy under ischemic conditions.…”

Aberrant hypermethylation ofmiR-9genes in gastric cancer

“…Recent studies have indicated that several miRNAs, including miR-34b/c, miR-129, miR-137, miR-181C, miR-199a, miR-212, miR-512 and miR-516, were dysregulated and showed aberrant methylation patterns in gastric cancer cells. 6,9,[14][15][16][17][18][19][20][21] The three pri-miR-9 transcripts are all located within non-protein coding transcripts (Fig. 2A).…”