Skip to main content

Advertisement

SpringerLink
Log in

c-Myc-induced, long, noncoding H19 affects cell proliferation and predicts a poor prognosis in patients with gastric cancer

  • Original Paper
  • Published:
Medical Oncology Aims and scope Submit manuscript

Abstract

Gastric cancer (GC) is one of the most frequent cancers worldwide. Recent studies have shown that long noncoding RNAs (lncRNAs) play critical roles in multiple biological processes, including oncogenesis. The present study aimed to evaluate the potential role of lncRNA H19 in GC. qRT-PCR was performed to investigate the expression of H19 in tumor tissues and corresponding non-tumor lung tissues from 80 patients with GC and in GC cell lines. The Kaplan–Meier method and Cox proportional hazards analysis were used to evaluate the association between H19 expression and overall survival time (OS). The biological significance of H19 was evaluated using siRNAs in vitro. We also constructed a c-Myc plasmid to investigate the cause of the altered expression of H19 in the progression of GC. The results show that lncRNA H19 is overexpressed in tumor tissues compared with adjacent normal tissues. An advanced tumor-node-metastasis stage was positively correlated with increased H19 expression (P < 0.001), and a high H19 expression was associated with poor OS and can be regarded as an independent predictor of the OS of GC patients (P = 0.042). MTT and colony formation assays confirmed that H19 expression affects GC cell proliferation in vitro. Furthermore, exogenous c-Myc significantly induces H19 expression, and the expression of H19 was positively correlated with the c-Myc levels in the 80 samples used in our study (Pearson correlation coefficient = −0.687). In conclusion, our study demonstrates that the altered expression of lncRNA H19, which is induced by c-Myc, is involved in the development and progression of GC by regulating cell proliferation and shows that H19 may be a potential diagnostic and prognostic target in patients with GC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60(5):277–300. doi:10.3322/caac.20073.

    Article  PubMed  Google Scholar 

  2. Karim-Kos HE, de Vries E, Soerjomataram I, Lemmens V, Siesling S, Coebergh JW. Recent trends of cancer in Europe: a combined approach of incidence, survival and mortality for 17 cancer sites since the 1990s. Eur J Cancer. 2008;44(10):1345–89. doi:10.1016/j.ejca.2007.12.015.

    Article  PubMed  Google Scholar 

  3. Amaral PP, Dinger ME, Mercer TR, Mattick JS. The eukaryotic genome as an RNA machine. Science. 2008;319(5871):1787–9. doi:10.1126/science.1155472.

    Article  CAS  PubMed  Google Scholar 

  4. Guttman M, Amit I, Garber M, French C, Lin MF, Feldser D, et al. Chromatin signature reveals over a thousand highly conserved large non-coding RNAs in mammals. Nature. 2009;458(7235):223–7. doi:10.1038/nature07672.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  5. Tzankov A, Gschwendtner A, Augustin F, Fiegl M, Obermann EC, Dirnhofer S, et al. Diffuse large B-cell lymphoma with overexpression of cyclin e substantiates poor standard treatment response and inferior outcome. Clin Cancer Res. 2006;12(7 Pt 1):2125–32. doi:10.1158/1078-0432.CCR-05-2135.

    Article  CAS  PubMed  Google Scholar 

  6. Gupta RA, Shah N, Wang KC, Kim J, Horlings HM, Wong DJ, et al. Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature. 2010;464(7291):1071–6. doi:10.1038/nature08975.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, et al. The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res. 2012;22(9):1775–89. doi:10.1101/gr.132159.111.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Lai MC, Yang Z, Zhou L, Zhu QQ, Xie HY, Zhang F, et al. Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation. Med Oncol. 2012;29(3):1810–6. doi:10.1007/s12032-011-0004-z.

    Article  CAS  PubMed  Google Scholar 

  9. Matouk IJ, Mezan S, Mizrahi A, Ohana P, Abu-Lail R, Fellig Y, et al. The oncofetal H19 RNA connection: hypoxia, p53 and cancer. Biochim Biophys Acta. 2010;1803(4):443–51. doi:10.1016/j.bbamcr.2010.01.010.

    Article  CAS  PubMed  Google Scholar 

  10. Benetatos L, Vartholomatos G, Hatzimichael E. MEG3 imprinted gene contribution in tumorigenesis. Int J Cancer. 2011;129(4):773–9. doi:10.1002/ijc.26052.

    Article  CAS  PubMed  Google Scholar 

  11. Gutschner T, Diederichs S. The hallmarks of cancer: a long non-coding RNA point of view. RNA Biol. 2012;9(6):703–19. doi:10.4161/rna.20481.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  12. Bartolomei MS, Zemel S, Tilghman SM. Parental imprinting of the mouse H19 gene. Nature. 1991;351(6322):153–5. doi:10.1038/351153a0.

    Article  CAS  PubMed  Google Scholar 

  13. Caspary T, Cleary MA, Baker CC, Guan XJ, Tilghman SM. Multiple mechanisms regulate imprinting of the mouse distal chromosome 7 gene cluster. Mol Cell Biol. 1998;18(6):3466–74.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Reid LH, Davies C, Cooper PR, Crider-Miller SJ, Sait SN, Nowak NJ, et al. A 1-Mb physical map and PAC contig of the imprinted domain in 11p15.5 that contains TAPA1 and the BWSCR1/WT2 region. Genomics. 1997;43(3):366–75. doi:10.1006/geno.1997.4826.

    Article  CAS  PubMed  Google Scholar 

  15. DeChiara TM, Robertson EJ, Efstratiadis A. Parental imprinting of the mouse insulin-like growth factor II gene. Cell. 1991;64(4):849–59.

    Article  CAS  PubMed  Google Scholar 

  16. Thorvaldsen JL, Duran KL, Bartolomei MS. Deletion of the H19 differentially methylated domain results in loss of imprinted expression of H19 and Igf2. Genes Dev. 1998;12(23):3693–702.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Luo M, Li Z, Wang W, Zeng Y, Liu Z, Qiu J. Upregulated H19 contributes to bladder cancer cell proliferation by regulating ID2 expression. FEBS J. 2013;280(7):1709–16. doi:10.1111/febs.12185.

    Article  CAS  PubMed  Google Scholar 

  18. Zhang L, Yang F, Yuan JH, Yuan SX, Zhou WP, Huo XS, et al. Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma. Carcinogenesis. 2013;34(3):577–86. doi:10.1093/carcin/bgs381.

    Article  PubMed  Google Scholar 

  19. Sorin V, Ohana P, Gallula J, Birman T, Matouk I, Hubert A, et al. H19-promoter-targeted therapy combined with gemcitabine in the treatment of pancreatic cancer. ISRN Oncol. 2012;2012:351750. doi:10.5402/2012/351750.

  20. Adriaenssens E, Dumont L, Lottin S, Bolle D, Lepretre A, Delobelle A, et al. H19 overexpression in breast adenocarcinoma stromal cells is associated with tumor values and steroid receptor status but independent of p53 and Ki-67 expression. Am J Pathol. 1998;153(5):1597–607. doi:10.1016/S0002-9440(10)65748-3.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Kondo M, Suzuki H, Ueda R, Osada H, Takagi K, Takahashi T. Frequent loss of imprinting of the H19 gene is often associated with its overexpression in human lung cancers. Oncogene. 1995;10(6):1193–8.

    CAS  PubMed  Google Scholar 

  22. Matouk IJ, DeGroot N, Mezan S, Ayesh S, Abu-lail R, Hochberg A, et al. The H19 non-coding RNA is essential for human tumor growth. PLoS One. 2007;2(9):e845. doi:10.1371/journal.pone.0000845.

    Article  PubMed Central  PubMed  Google Scholar 

  23. Barsyte-Lovejoy D, Lau SK, Boutros PC, Khosravi F, Jurisica I, Andrulis IL, et al. The c-Myc oncogene directly induces the H19 noncoding RNA by allele-specific binding to potentiate tumorigenesis. Cancer Res. 2006;66(10):5330–7. doi:10.1158/0008-5472.CAN-06-0037.

    Article  CAS  PubMed  Google Scholar 

  24. Gao WL, Liu M, Yang Y, Yang H, Liao Q, Bai Y, et al. The imprinted H19 gene regulates human placental trophoblast cell proliferation via encoding miR-675 that targets Nodal Modulator 1 (NOMO1). RNA Biol. 2012;9(7):1002–10. doi:10.4161/rna.20807.

    Article  CAS  PubMed  Google Scholar 

  25. Nie L, Wu HJ, Hsu JM, Chang SS, Labaff AM, Li CW, et al. Long non-coding RNAs: versatile master regulators of gene expression and crucial players in cancer. Am J Transl Res. 2012;4(2):127–50.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Prensner JR, Rubin MA, Wei JT, Chinnaiyan AM. Beyond PSA: the next generation of prostate cancer biomarkers. Sci Transl Med. 2012;4(127):127rv3. doi:10.1126/scitranslmed.3003180.

    Article  PubMed Central  PubMed  Google Scholar 

  27. Salagierski M, Schalken JA. Molecular diagnosis of prostate cancer: PCA3 and TMPRSS2: ERG gene fusion. J Urol. 2012;187(3):795–801. doi:10.1016/j.juro.2011.10.133.

    CAS  PubMed  Google Scholar 

  28. Yang Z, Zhou L, Wu LM, Lai MC, Xie HY, Zhang F, et al. Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation. Ann Surg Oncol. 2011;18(5):1243–50. doi:10.1245/s10434-011-1581-y.

    Article  PubMed  Google Scholar 

  29. Orom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G, et al. Long noncoding RNAs with enhancer-like function in human cells. Cell. 2010;143(1):46–58. doi:10.1016/j.cell.2010.09.001.

    Article  CAS  PubMed  Google Scholar 

  30. Khalil AM, Guttman M, Huarte M, Garber M, Raj A, Rivea Morales D, et al. Many human large intergenic noncoding RNAs associate with chromatin-modifying complexes and affect gene expression. Proc Natl Acad Sci USA. 2009;106(28):11667–72. doi:10.1073/pnas.0904715106.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Nesbit CE, Tersak JM, Prochownik EV. MYC oncogenes and human neoplastic disease. Oncogene. 1999;18(19):3004–16. doi:10.1038/sj.onc.1202746.

    Article  CAS  PubMed  Google Scholar 

  32. McMahon SB, Van Buskirk HA, Dugan KA, Copeland TD, Cole MD. The novel ATM-related protein TRRAP is an essential cofactor for the c-Myc and E2F oncoproteins. Cell. 1998;94(3):363–74.

    Article  CAS  PubMed  Google Scholar 

  33. Eberhardy SR, Farnham PJ. Myc recruits P-TEFb to mediate the final step in the transcriptional activation of the cad promoter. J Biol Chem. 2002;277(42):40156–62. doi:10.1074/jbc.M207441200.

    Article  CAS  PubMed  Google Scholar 

  34. Orian A, van Steensel B, Delrow J, Bussemaker HJ, Li L, Sawado T, et al. Genomic binding by the Drosophila Myc, Max, Mad/Mnt transcription factor network. Genes Dev. 2003;17(9):1101–14. doi:10.1101/gad.1066903.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Mao DY, Watson JD, Yan PS, Barsyte-Lovejoy D, Khosravi F, Wong WW, et al. Analysis of Myc bound loci identified by CpG island arrays shows that Max is essential for Myc-dependent repression. Curr Biol. 2003;13(10):882–6.

    Article  CAS  PubMed  Google Scholar 

  36. Li Z, Van Calcar S, Qu C, Cavenee WK, Zhang MQ, Ren B. A global transcriptional regulatory role for c-Myc in Burkitt’s lymphoma cells. Proc Natl Acad Sci USA. 2003;100(14):8164–9. doi:10.1073/pnas.1332764100.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Fernandez PC, Frank SR, Wang L, Schroeder M, Liu S, Greene J, et al. Genomic targets of the human c-Myc protein. Genes Dev. 2003;17(9):1115–29. doi:10.1101/gad.1067003.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

Download references

Conflict of interest

The authors have declared that no conflicts of interest exist.

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China

    Er-Bao Zhang, Rong Kong & Wei De

  2. Department of Oncology, Xuzhou Central Hospital, Affiliated Xuzhou Hospital, College of Medicine, Southeast University, Xuzhou, Jiangsu, China

    Liang Han

  3. Central Laboratory, The Second Affiliated Hospital of Southeast University, Nanjing, China

    Dan-Dan Yin

  4. Department of Oncology, Nanjing First Hospital, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China

    Jinfei Chen

Authors
  1. Er-Bao Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Liang Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dan-Dan Yin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rong Kong
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wei De
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jinfei Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Wei De or Jinfei Chen.

Additional information

Er-Bao Zhang, Liang Han, and Dan-Dan Yin have contributed equally to this work and should be regarded as joint first authors.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zhang, EB., Han, L., Yin, DD. et al. c-Myc-induced, long, noncoding H19 affects cell proliferation and predicts a poor prognosis in patients with gastric cancer. Med Oncol 31, 914 (2014). https://doi.org/10.1007/s12032-014-0914-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12032-014-0914-7

Keywords

Search

Navigation