Original Article | Published:

Long noncoding RNA BC032469, a novel competing endogenous RNA, upregulates hTERT expression by sponging miR-1207-5p and promotes proliferation in gastric cancer

Oncogene volume 35, pages 35243534 (07 July 2016) | Download Citation

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Abstract

Long noncoding RNAs (lncRNAs) are emerging as new players in gene regulation and are associated with the development of cancers. To investigate the important role and mechanism of lncRNAs in the progression of gastric cancer, we screened lncRNAs in gastric cancer tissues and corresponding adjacent tissues, and assessed the effects on gastric cancer. Here, we report that BC032469, a novel lncRNA, expressed highly in gastric cancer tissues, and the upregulation was clinically associated with larger tumor size, poor differentiation and shorter survival of gastric cancer patients. Downregulation of BC032469 resulted in a significant inhibition of proliferation in vitro and in vivo. Mechanistically, BC032469 could directly bind to miR-1207-5p and effectively functioned as a sponge for miR-1207-5p to modulate the derepression of hTERT. Thus, BC032469 may function as a ceRNA to impair miR-1207-5p-dependent hTERT downregulation, suggesting that it may be clinically valuable as a poor prognostic biomarker of gastric cancer.

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References

  1. 1.

    , , , , , et al. Gastric cancer mortality in a high incidence area: long-term follow-up of Helicobacter pylori-related precancerous lesions in the general population. Arch Iran Med 2013; 16: 343–347.

  2. 2.

    , , . Analysis of telomerase activity and detection of its catalytic subunit, hTERT. Anal Biochem 2003; 315: 1–21.

  3. 3.

    , . Telomeres and aging. Physiol Rev 2008; 88: 557–579.

  4. 4.

    , , , , , et al. Knockdown of p53 combined with expression of the catalytic subunit of telomerase is sufficient to immortalize primary human ovarian surface epithelial cells. Carcinogenesis 2007; 28: 174–182.

  5. 5.

    , , , , , . hTERT promotes the invasion of telomerase-negative tumor cells in vitro. Int J Oncol 2009; 35: 329–336.

  6. 6.

    , , , , , . Prognostic role of telomerase activity in gastric adenocarcinoma: a meta-analysis. Exp Ther Med 2012; 3: 728–734.

  7. 7.

    , , , , , et al. The imprinted H19 lncRNA antagonizes let-7 microRNAs. Mol Cell 2013; 52: 101–112.

  8. 8.

    , , , , , et al. miR-27b represses migration of mouse MSCs to burned margins and prolongs wound repair through silencing SDF-1a. PLoS One 2013; 8: e68972.

  9. 9.

    , , , , , et al. miR-1207-5p and miR-1266 suppress gastric cancer growth and invasion by targeting telomerase reverse transcriptase. Cell Death Dis 2014; 5: e1034.

  10. 10.

    , . Regulation of reproductive development by non-coding RNA in Arabidopsis: to flower or not to flower. J Plant Res 2012; 125: 693–704.

  11. 11.

    , , . Evolution and functions of long noncoding RNAs. Cell 2009; 136: 629–641.

  12. 12.

    , , , , . Long non-coding RNAs: a new frontier in the study of human diseases. Cancer Lett 2013; 339: 159–166.

  13. 13.

    , , , , . A ceRNA hypothesis: the Rosetta Stone of a hidden RNA language? Cell 2011; 146: 353–358.

  14. 14.

    , , , , , et al. A long noncoding RNA controls muscle differentiation by functioning as a competing endogenous RNA. Cell 2011; 147: 358–369.

  15. 15.

    , , , , , . Up-regulated long non-coding RNA H19 contributes to proliferation of gastric cancer cells. FEBS J 2012; 279: 3159–3165.

  16. 16.

    , , , , , et al. Target mimicry provides a new mechanism for regulation of microRNA activity. Nat Genet 2007; 39: 1033–1037.

  17. 17.

    , , , , , et al. CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer. Nucleic Acids Res 2010; 38: 5366–5383.

  18. 18.

    , , , , , et al. Genome-wide analysis of mammalian promoter architecture and evolution. Nat Genet 2006; 38: 626–635.

  19. 19.

    , , , , , . Evf2 (Dlx6as) lncRNA regulates ultraconserved enhancer methylation and the differential transcriptional control of adjacent genes. Development 2013; 140: 4407–4416.

  20. 20.

    , . Perfect seed pairing is not a generally reliable predictor for miRNA-target interactions. Nat Struct Mol Biol 2006; 13: 849–851.

  21. 21.

    , , , , , et al. Molecular characterization of human Argonaute-containing ribonucleoprotein complexes and their bound target mRNAs. RNA 2008; 14: 2580–2596.

  22. 22.

    , . Micromanagers of gene expression: the potentially widespread influence of metazoan microRNAs. Nat Rev Genet 2004; 5: 396–400.

  23. 23.

    . Redefining microRNA targets. Curr Biol 2009; 19: 870–873.

  24. 24.

    , , . Down-regulation of a host microRNA by a Herpesvirus saimiri noncoding RNA. Science 2010; 328: 1563–1566.

  25. 25.

    , , , , , et al. Expression of versican 3'-untranslated region modulates endogenous microRNA functions. PLoS One 2010; 5: e13599.

  26. 26.

    , , , , , et al. Cancer-associated regulation of alternative splicing. Nat Struct Mol Biol 2009; 16: 670–676.

  27. 27.

    , , , , . The C. elegans microRNA let-7 binds to imperfect let-7 complementary sites from the lin-41 3'UTR. Genes Dev 2004; 18: 132–137.

  28. 28.

    . Computational methods to identify miRNA targets. Semin Cell Dev Biol 2010; 21: 738–744.

  29. 29.

    , , . MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat Methods 2007; 4: 721–726.

  30. 30.

    , , , , . MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation. Nature 2008; 455: 1124–1128.

  31. 31.

    , , , , , et al. Noninvasive and real-time monitoring of the therapeutic response of tumors in vivo with an optimized hTERT promoter. Cancer 2012; 118: 1884–1893.

  32. 32.

    , . Degradation of microRNAs by a family of exoribonucleases in Arabidopsis. Science 2008; 321: 1490–1492.

  33. 33.

    , , . Adenylation of plant miRNAs. Nucleic Acids Res 2009; 37: 1878–1885.

  34. 34.

    , , , , , . Icariin and icaritin stimulate the proliferation of SKBr3 cells through the GPER1-mediated modulation of the EGFR-MAPK signaling pathway. Int J Mol Med 2014; 33: 1627–1634.

  35. 35.

    , , , , , et al. Negative regulation of lncRNA GAS5 by miR-21. Cell Death Differ 2013; 20: 1558–1568.

  36. 36.

    , , , , , et al. Melatonin inhibits cell growth and migration, but promotes apoptosis in gastric cancer cell line, SGC7901. Biotech Histochem 2013; 88: 281–289.

  37. 37.

    , , . Chlamydia trachomatis inhibits telomeric DNA damage signaling via transient hTERT upregulation. Int J Med Microbiol 2013; 303: 463–474.

  38. 38.

    , , , , . Miniaturized fluorescent RNA dot blot method for rapid quantitation of gene expression. BMC Biotechnol 2004; 4: 12.

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Acknowledgements

This study was supported by the National Natural Science Foundation of China (No. 81201950) and Luzhou Medical University Funding (No. 2014ZD-001). We thank Professor Xia Zhang for suggestions on the manuscript.

Author information

Author notes

    • M-H Lü
    •  & B Tang

    These authors contributed equally to this work.

Affiliations

  1. Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing, China

    • M-H Lü
    • , B Tang
    • , S Zeng
    • , C-J Hu
    • , R Xie
    • , Y-Y Wu
    • , S-M Wang
    •  & S-M Yang
  2. Department of Gastroenterology, The Affiliated Hospital of Luzhou Medical College, Luzhou, China

    • M-H Lü
  3. Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Third Military Medical University, Chongqing, China

    • F-T He

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Competing interests

The authors declare no conflict of interest.

Corresponding author

Correspondence to S-M Yang.

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DOI

https://doi.org/10.1038/onc.2015.413

Supplementary Information accompanies this paper on the Oncogene website (http://www.nature.com/onc)

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