Abstract
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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Bejerano G, Pheasant M, Makunin I, Stephen S, Kent WJ, Mattick JS et al. Ultraconserved elements in the human genome. Science 2004; 304: 1321–1325.
Calin GA, Croce CM . MicroRNA signatures in human cancers. Nat Rev Cancer 2006; 6: 857–866.
Esteller M . Non-coding RNAs in human disease. Nat Rev Genet 2011; 12: 861–874.
Calin GA, Liu CG, Ferracin M, Hyslop T, Spizzo R, Sevignani C et al. Ultraconserved regions encoding ncRNAs are altered in human leukemias and carcinomas. Cancer Cell 2007; 12: 215–229.
Braconi C, Valeri N, Kogure T, Gasparini P, Huang N, Nuovo GJ et al. Expression and functional role of a transcribed noncoding RNA with an ultraconserved element in hepatocellular carcinoma. Proc Natl Acad Sci USA 2011; 108: 786–791.
Hudson RS, Yi M, Volfovsky N, Prueitt RL, Esposito D, Volinia S et al. Transcription signatures encoded by ultraconserved genomic regions in human prostate cancer. Mol Cancer 2013; 12: 13.
Scaruffi P, Stigliani S, Moretti S, Coco S, De Vecchi C, Valdora F et al. Transcribed-ultra conserved region expression is associated with outcome in high-risk neuroblastoma. BMC Cancer 2009; 9: 441.
Mestdagh P, Fredlund E, Pattyn F, Rihani A, Van Maerken T, Vermeulen J et al. An integrative genomics screen uncovers ncRNA T-UCR functions in neuroblastoma tumours. Oncogene 2010; 29: 3583–3592.
Watters KM, Bryan K, Foley NH, Meehan M, Stallings RL . Expressional alterations in functional ultra-conserved non-coding RNAs in response to all-trans retinoic acid-induced differentiation in neuroblastoma cells. BMC Cancer 2013; 13: 184.
Lujambio A, Portela A, Liz J, Melo SA, Rossi S, Spizzo R et al. CpG island hypermethylation-associated silencing of non-coding RNAs transcribed from ultraconserved regions in human cancer. Oncogene 2010; 29: 6390–6401.
Liz J, Portela A, Soler M, Gomez A, Ling H, Michlewski G et al. Regulation of pri-miRNA processing by a long noncoding RNA transcribed from an ultraconserved region. Mol Cell 2014; 55: 138–147.
Oue N, Sentani K, Sakamoto N, Yasui W . Clinicopathologic and molecular characteristics of gastric cancer showing gastric and intestinal mucin phenotype. Cancer Sci 2015; 106: 951–958.
Sakamoto N, Naito Y, Oue N, Sentani K, Uraoka N, Zarni Oo H et al. MicroRNA-148a is downregulated in gastric cancer, targets MMP7, and indicates tumor invasiveness and poor prognosis. Cancer Sci 2014; 105: 236–243.
Naito Y, Yasuno K, Tagawa H, Sakamoto N, Oue N, Yashiro M et al. MicroRNA-145 is a potential prognostic factor of scirrhous type gastric cancer. Oncol Rep 2014; 32: 1720–1726.
Naito Y, Sakamoto N, Oue N, Yashiro M, Sentani K, Yanagihara K et al. MicroRNA-143 regulates collagen type III expression in stromal fibroblasts of scirrhous type gastric cancer. Cancer Sci 2014; 105: 228–235.
Xu J, Liao X, Lu N, Liu W, Wong CW . Chromatin-modifying drugs induce miRNA-153 expression to suppress Irs-2 in glioblastoma cell lines. Int J Cancer 2011; 129: 2527–2531.
Xu Q, Sun Q, Zhang J, Yu J, Chen W, Zhang Z . Downregulation of miR-153 contributes to epithelial–mesenchymal transition and tumor metastasis in human epithelial cancer. Carcinogenesis 2013; 34: 539–549.
Yuan Y, Du W, Wang Y, Xu C, Wang J, Zhang Y et al. Suppression of AKT expression by miR-153 produced anti-tumor activity in lung cancer. Int J Cancer 2015; 136: 1333–1340.
Kim TH, Kim YK, Kwon Y, Heo JH, Kang H, Kim G et al. Deregulation of miR-519a, 153, and 485-5p and its clinicopathological relevance in ovarian epithelial tumours. Histopathology 2010; 57: 734–743.
Zhang Z, Sun J, Bai Z, Li H, He S, Chen R et al. MicroRNA-153 acts as a prognostic marker in gastric cancer and its role in cell migration and invasion. Onco Targets Ther 2015; 8: 357–364.
Zhang L, Pickard K, Jenei V, Bullock MD, Bruce A, Mitter R et al. miR-153 supports colorectal cancer progression via pleiotropic effects that enhance invasion and chemotherapeutic resistance. Cancer Res 2013; 73: 6435–6447.
Wu Z, He B, He J, Mao X . Upregulation of miR-153 promotes cell proliferation via downregulation of the PTEN tumor suppressor gene in human prostate cancer. Prostate 2013; 73: 596–604.
Firth SM, Baxter RC . Cellular actions of the insulin-like growth factor binding proteins. Endocr Rev 2002; 23: 824–854.
Baxter RC . IGF binding proteins in cancer: mechanistic and clinical insights. Nat Rev Cancer 2014; 14: 329–341.
Bach LA . IGFBP-6 five years on; not so 'forgotten'? Growth Horm IGF Res 2005; 15: 185–192.
Bach LA, Fu P, Yang Z . Insulin-like growth factor-binding protein-6 and cancer. Clin Sci (Lond) 2013; 124: 215–229.
Gehring WJ, Hiromi Y . Homeotic genes and the homeobox. Annu Rev Genet 1986; 20: 147–173.
Volpe MV, Pham L, Lessin M, Ralston SJ, Bhan I, Cutz E et al. Expression of Hoxb-5 during human lung development and in congenital lung malformations. Birth Defects Res A 2003; 67: 550–556.
Fu M, Lui VC, Sham MH, Cheung AN, Tam PK . HOXB5 expression is spatially and temporarily regulated in human embryonic gut during neural crest cell colonization and differentiation of enteric neuroblasts. Dev Dyn 2003; 228: 1–10.
Hur H, Lee JY, Yun HJ, Park BW, Kim MH . Analysis of HOX gene expression patterns in human breast cancer. Mol Biotechnol 2014; 56: 64–71.
Morgan R, Plowright L, Harrington KJ, Michael A, Pandha HS . Targeting HOX and PBX transcription factors in ovarian cancer. BMC Cancer 2010; 10: 89.
Luo J, Cai Q, Wang W, Huang H, Zeng H, He W et al. A microRNA-7 binding site polymorphism in HOXB5 leads to differential gene expression in bladder cancer. PLoS One 2012; 7: e40127.
Fischbach NA, Rozenfeld S, Shen W, Fong S, Chrobak D, Ginzinger D et al. HOXB6 overexpression in murine bone marrow immortalizes a myelomonocytic precursor in vitro and causes hematopoietic stem cell expansion and acute myeloid leukemia in vivo. Blood 2005; 105: 1456–1466.
Oue N, Hamai Y, Mitani Y, Matsumura S, Oshimo Y, Aung PP et al. Gene expression profile of gastric carcinoma: identification of genes and tags potentially involved in invasion, metastasis, and carcinogenesis by serial analysis of gene expression. Cancer Res 2004; 64: 2397–2405.
Goto K, Oue N, Shinmei S, Sentani K, Sakamoto N, Naito Y et al. Expression of miR-486 is a potential prognostic factor after nephrectomy in advanced renal cell carcinoma. Mol Clin Oncol 2013; 1: 235–240.
Oue N, Anami K, Schetter AJ, Moehler M, Okayama H, Khan MA et al. High miR-21 expression from FFPE tissues is associated with poor survival and response to adjuvant chemotherapy in colon cancer. Int J Cancer 2014; 134: 1926–1934.
Oue N, Oshimo Y, Nakayama H, Ito R, Yoshida K, Matsusaki K et al. DNA methylation of multiple genes in gastric carcinoma: association with histological type and CpG island methylator phenotype. Cancer Sci 2003; 94: 901–905.
Matsumura S, Oue N, Mitani Y, Kitadai Y, Yasui W . DNA demethylation of vascular endothelial growth factor-C is associated with gene expression and its possible involvement of lymphangiogenesis in gastric cancer. Int J Cancer 2007; 120: 1689–1695.
Naito Y, Oue N, Pham TT, Yamamoto M, Fujihara M, Ishida T et al. Characteristic miR-24 expression in gastric cancers among atomic bomb survivors. Pathobiology 2015; 82: 68–75.
Oue N, Naito Y, Hayashi T, Takigahira M, Kawano-Nagatsuma A, Sentani K et al. Signal peptidase complex 18, encoded by SEC11A, contributes to progression via TGF-alpha secretion in gastric cancer. Oncogene 2014; 33: 3918–3926.
Acknowledgements
We thank Mr Shinichi Norimura for his excellent technical assistance. This work was carried out with the kind cooperation of the Research Center for Molecular Medicine of the Faculty of Medicine of Hiroshima University. We also thank the Analysis Center of Life Science of Hiroshima University for the use of their facilities. This work was supported, in part, by grants-in-aid for Cancer Research from the Ministry of Education, Culture, Science, Sports and Technology of Japan, and, in part, by a grant-in-aid for the Third Comprehensive. 10-Year Strategy for Cancer Control from the Ministry of Health, Labor and Welfare of Japan, by the National Institute of Biomedical Innovation (Program for Promotion of Fundamental Studies in Health Sciences), and by the National Cancer Center Research and Development Fund.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
Goto, K., Ishikawa, S., Honma, R. et al. The transcribed-ultraconserved regions in prostate and gastric cancer: DNA hypermethylation and microRNA-associated regulation. Oncogene 35, 3598–3606 (2016). https://doi.org/10.1038/onc.2015.445
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2015.445
This article is cited by
-
The role of miR-153 and related upstream/downstream pathways in cancers: from a potential biomarker to treatment of tumor resistance and a therapeutic target
Medical Oncology (2022)
-
Uc.63+ contributes to gastric cancer progression through regulation of NF-kB signaling
Gastric Cancer (2020)
-
Long non-coding RNA in stem cell pluripotency and lineage commitment: functions and evolutionary conservation
Cellular and Molecular Life Sciences (2019)
-
Uc.416 + A promotes epithelial-to-mesenchymal transition through miR-153 in renal cell carcinoma
BMC Cancer (2018)
-
Re-expression of microRNA-4319 inhibits growth of prostate cancer via Her-2 suppression
Clinical and Translational Oncology (2018)