The transcribed-ultraconserved regions in prostate and gastric cancer: DNA hypermethylation and microRNA-associated regulation

• Published in: Oncogene 2016-07, Vol.35 (27), p.3598-3606
• Main Authors: Goto, K, Ishikawa, S, Honma, R, Tanimoto, K, Sakamoto, N, Sentani, K, Oue, N, Teishima, J, Matsubara, A, Yasui, W
• Format: Article
• Language: English
• Subjects: 38/109; 38/89; 45/23; 45/77; 631/337/384; Adult; Aged; Aged, 80 and over; Apoptosis; Azacitidine - pharmacology; Azacytidine; Binding sites; Bisulfite; Cell Biology; Cell growth; Cell Line, Tumor; Cell Proliferation - genetics; Conserved Sequence - genetics; CpG islands; Development and progression; DNA Methylation; DNA, Neoplasm - genetics; Down-Regulation - drug effects; Enzyme Inhibitors - pharmacology; Female; Gastric cancer; Gene Expression Profiling - methods; Gene Expression Regulation, Neoplastic; Genetic aspects; Genetic transcription; Health aspects; Human Genetics; Humans; Insulin; Insulin-like growth factor-binding protein 6; Internal Medicine; Male; Medicine; Medicine & Public Health; MicroRNA; MicroRNAs; MicroRNAs - genetics; Middle Aged; miRNA; Oncology; original-article; Polymerase chain reaction; Promoter Regions, Genetic - genetics; Properties; Prostate; Prostate cancer; Prostatic Neoplasms - genetics; Prostatic Neoplasms - pathology; Reporter gene; Reverse Transcriptase Polymerase Chain Reaction; Reverse transcription; Stomach Neoplasms - genetics; Stomach Neoplasms - pathology; Transcription factors
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.445

The transcribed-ultraconserved regions (T-UCRs) are a novel class of non-coding RNAs, which are absolutely conserved (100%) between the orthologous regions of the human, rat and mouse genomes. Previous studies have described that several T-UCRs show differential expressions in cancers and might be involved in cancer development. We investigated the transcriptional levels of representative 26 T-UCRs and determined the regions that were differently expressed in prostate cancer (PCa) and gastric cancer (GC). A quantitative reverse transcription-polymerase chain reaction analysis revealed the downregulation of Uc.158+A expression by a DNA methylation-associated mechanism, which was restored by 5-Aza-dC (5-aza-2′-deoxycytidine) treatment. Bisulfite genomic sequencing using cell lines and tissue samples demonstrated cancer-specific CpG hypermethylation in both GC and PCa. However, Uc.416+A was only overexpressed in GC and we identified an miR-153 binding site in the possible regulatory region of Uc.416+A using online databases. Along with a forced expression or knockdown of miR-153 in MKN-74 GC cells, the transcriptional levels of Uc.416+A were significantly disturbed. A luciferase reporter gene assay supported the direct regulation of Uc.416+A expression by miR-153. Furthermore, Uc.416+A was associated with cell growth through the regulation of IGFBP6 (insulin-like growth factor-binding protein 6) in GC. These findings suggest an oncogenic role of Uc.416+A in GC, which suggests that our approach would provide new insights into functional studies of T-UCRs in cancer biology.