Methylation of an intronic region regulates miR-199a in testicular tumor malignancy
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 microRNAs 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 …
methylated regions were located in introns or intergenic regions, and postulated these might
regulate non-coding RNAs. Three microRNAs 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 …
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 microRNAs 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.
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