Skip to main content

Advertisement

SpringerLink
Log in

H. pylori eradication did not improve dysregulation of specific oncogenic miRNAs in intestinal metaplastic glands

  • Original Article—Alimentary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

Many microRNAs (miRNAs) are differentially expressed in Helicobacter pylori-infected gastric mucosa and in gastric cancer tissue.

Aim

We aimed to compare the effect of H. pylori eradication on gastric mucosal miRNAs in subjects in a high-risk group for gastric cancer compared to controls.

Methods

Patients with a recent history of endoscopic resection for early gastric cancer and sex- and age-matched non-cancer controls were enrolled. The expression of 21 miRNAs was examined using gastric mucosal biopsy specimens and microdissected gastric glands from the lesser and greater curvatures of the gastric corpus both before and one year after H. pylori eradication.

Results

Twenty patients and 14 controls were enrolled. The expression of oncogenic miRNAs (miR-17/92 and the miR-106b-93-25 cluster, miR-21, miR-194, and miR-196) was significantly higher in the gastric mucosa of the cancer group than in the controls. H. pylori eradication resulted in a significant fall in the expression of oncogenic miRNAs only in the controls, whereas miR-223 expression was decreased and let-7d expression was increased in both groups. miR-196 was expressed only in intestinal metaplastic glands. The expression of oncogenic miRNAs was significantly higher in the intestinal metaplastic glands than in the non-intestinal metaplastic glands irrespective of H. pylori eradication. In neither group did H. pylori eradication significantly change any miRNA expression in the intestinal metaplastic glands.

Conclusion

Dysregulation of specific miRNAs is present in H. pylori-induced corpus gastritis. H. pylori eradication improved miRNA dysregulation, but not in intestinal metaplastic glands or in the gastric mucosa of patients in a high-risk group for gastric cancer.

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

Similar content being viewed by others

References

  1. Hammond SM, Bernstein E, Beach D, Hannon GJ. An RNA-directed nuclease mediates post-transcriptional gene silencing in Drosophila cells. Nature. 2000;404:293–6.

    Article  PubMed  CAS  Google Scholar 

  2. Lee RC, Feinbaum RL, Ambros V. The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 1993;75:843–54.

    Article  PubMed  CAS  Google Scholar 

  3. Wu WK, Lee CW, Cho CH, Fan D, Wu K, Yu J, et al. MicroRNA dysregulation in gastric cancer: a new player enters the game. Oncogene. 2010;29:5761–71.

    Google Scholar 

  4. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell. 2009;136:215–33.

    Article  PubMed  CAS  Google Scholar 

  5. Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, et al. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834–8.

    Article  PubMed  CAS  Google Scholar 

  6. Wang J, Wang Q, Liu H, Hu B, Zhou W, Cheng Y. MicroRNA expression and its implication for the diagnosis and therapeutic strategies of gastric cancer. Cancer Lett. 2010;297:137–43.

    Article  PubMed  CAS  Google Scholar 

  7. Belair C, Darfeuille F, Staedel C. Helicobacter pylori and gastric cancer: possible role of microRNAs in this intimate relationship. Clin Microbiol Infect. 2009;15:806–12.

    Article  PubMed  CAS  Google Scholar 

  8. Petrocca F, Visone R, Onelli MR, Shah MH, Nicoloso MS, de Martino I, et al. E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. Cancer Cell. 2008;13:272–86.

    Article  PubMed  CAS  Google Scholar 

  9. Kim YK, Yu J, Han TS, Park SY, Namkoong B, Kim DH, et al. Functional links between clustered microRNAs: suppression of cell-cycle inhibitors by microRNA clusters in gastric cancer. Nucleic Acids Res. 2009;37:1672–81.

    Article  PubMed  CAS  Google Scholar 

  10. Mendell JT. miRiad roles for the miR-17-92 cluster in development and disease. Cell. 2008;133:217–22.

    Article  PubMed  CAS  Google Scholar 

  11. Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T. MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology. 2007;133:647–58.

    Article  PubMed  CAS  Google Scholar 

  12. Zhang L, Volinia S, Bonome T, Calin GA, Greshock J, Yang N, et al. Genomic and epigenetic alterations deregulate microRNA expression in human epithelial ovarian cancer. Proc Natl Acad Sci USA. 2008;105:7004–9.

    Article  PubMed  CAS  Google Scholar 

  13. Zhu S, Si ML, Wu H, Mo YY. MicroRNA-21 targets the tumor suppressor gene tropomyosin 1 (TPM1). J Biol Chem. 2007;282:14328–36.

    Article  PubMed  CAS  Google Scholar 

  14. Bueno MJ, Perez de Castro I, Gomez de Cedron M, Santos J, Calin GA, et al. Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression. Cancer Cell. 2008;13:496–506.

    Article  PubMed  CAS  Google Scholar 

  15. Furuta M, Kozaki KI, Tanaka S, Arii S, Imoto I, Inazawa J. miR-124 and miR-203 are epigenetically silenced tumor-suppressive microRNAs in hepatocellular carcinoma. Carcinogenesis. 2010;31:766–76.

    Article  PubMed  CAS  Google Scholar 

  16. Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, et al. RAS is regulated by the let-7 microRNA family. Cell. 2005;120:635–47.

    Article  PubMed  CAS  Google Scholar 

  17. Mayr C, Hemann MT, Bartel DP. Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science. 2007;315:1576–9.

    Article  PubMed  CAS  Google Scholar 

  18. Sampson VB, Rong NH, Han J, Yang Q, Aris V, Soteropoulos P, et al. MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells. Cancer Res. 2007;67:9762–70.

    Article  PubMed  CAS  Google Scholar 

  19. Burk U, Schubert J, Wellner U, Schmalhofer O, Vincan E, Spaderna S, et al. A reciprocal repression between ZEB1 and members of the miR-200 family promotes EMT and invasion in cancer cells. EMBO Rep. 2008;9:582–9.

    Article  PubMed  CAS  Google Scholar 

  20. Gregory PA, Bert AG, Paterson EL, Barry SC, Tsykin A, Farshid G, et al. The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 2008;10:593–601.

    Article  PubMed  CAS  Google Scholar 

  21. Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008;22:894–907.

    Article  PubMed  CAS  Google Scholar 

  22. Matsushima K, Isomoto H, Inoue N, Nakayama T, Hayashi T, Nakayama M, et al. MicroRNA signatures in Helicobacter pylori-infected gastric mucosa. Int J Cancer. 2011;128:361–70.

    Article  PubMed  CAS  Google Scholar 

  23. Shiotani A, Murao T, Uedo N, Iishi H, Yamanaka Y, Kamada T, et al. Eradication of H. pylori did not improve abnormal Sonic Hedgehog expression in the high risk group for gastric cancer. Dig Dis Sci. 2012;57:643–9.

    Article  PubMed  Google Scholar 

  24. Baldini L, Pretolani S, Bonvicini F, Miglio F, Epifanio G, Gentiloni Silveri N, et al. Effect of Helicobacter pylori infection, age and epithelial cell turnover in a general population at high risk for gastric cancer. Panminerva Med. 1999;41:187–92.

    PubMed  CAS  Google Scholar 

  25. Lynch DA, Mapstone NP, Clarke AM, Jackson P, Moayyedi P, Dixon MF, et al. Correlation between epithelial cell proliferation and histological grading in gastric mucosa. J Clin Pathol. 1999;52:367–71.

    Article  PubMed  CAS  Google Scholar 

  26. Sougioultzis S, Foukas PG, Tzivras M, Kourtessas D, Gorgoulis VG, Davaris P, et al. Alterations in the proliferating compartment of gastric mucosa during Helicobacter pylori infection: the putative role of epithelial cells expressing p27(kip1). Mod Pathol. 2003;16:1076–85.

    Article  PubMed  Google Scholar 

  27. Shiotani A, Iishi H, Ishiguro S, Tatsuta M, Nakae Y, Merchant JL. Epithelial cell turnover in relation to ongoing damage of the gastric mucosa in patients with early gastric cancer: increase of cell proliferation in paramalignant lesions. J Gastroenterol. 2005;40:337–44.

    Article  PubMed  Google Scholar 

  28. Popovic R, Riesbeck LE, Velu CS, Chaubey A, Zhang J, Achille NJ, et al. Regulation of mir-196b by MLL and its overexpression by MLL fusions contributes to immortalization. Blood. 2009;113:3314–22.

    Article  PubMed  CAS  Google Scholar 

  29. Chen C, Zhang Y, Zhang L, Weakley SM, Yao Q. MicroRNA-196: critical roles and clinical applications in development and cancer. J Cell Mol Med. 2011;15:14–23.

    Article  PubMed  CAS  Google Scholar 

  30. Hornstein E, Mansfield JH, Yekta S, Hu JK, Harfe BD, McManus MT, et al. The microRNA miR-196 acts upstream of Hoxb8 and Shh in limb development. Nature. 2005;438:671–4.

    Article  PubMed  CAS  Google Scholar 

  31. Hammerschmidt M, Brook A, McMahon AP. The world according to hedgehog. Trends Genet. 1997;13:14–21.

    Article  PubMed  CAS  Google Scholar 

  32. Bitgood MJ, McMahon AP. Hedgehog and Bmp genes are coexpressed at many diverse sites of cell–cell interaction in the mouse embryo. Dev Biol. 1995;172:126–38.

    Article  PubMed  CAS  Google Scholar 

  33. Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, et al. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell. 1993;75:1417–30.

    Article  PubMed  CAS  Google Scholar 

  34. Shiotani A, Nishi R, Uedo N, Iishi H, Tsutsui H, Ishii M, et al. Helicobacter pylori eradication prevents extension of intestinalization even in the high-risk group for gastric cancer. Digestion. 2010;81:223–30.

    Article  PubMed  Google Scholar 

  35. Shiotani A, Uedo N, Iishi H, Tatsuta M, Ishiguro S, Nakae Y, et al. Re-expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia. Int J Cancer. 2007;121:1182–9.

    Article  PubMed  CAS  Google Scholar 

  36. Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF, Wong N. MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology. 2008;135:257–69.

    Article  PubMed  CAS  Google Scholar 

  37. Zhang Z, Li Z, Gao C, Chen P, Chen J, Liu W, et al. miR-21 plays a pivotal role in gastric cancer pathogenesis and progression. Lab Invest. 2008;88:1358–66.

    Article  PubMed  CAS  Google Scholar 

  38. Xiao B, Guo J, Miao Y, Jiang Z, Huan R, Zhang Y, et al. Detection of miR-106a in gastric carcinoma and its clinical significance. Clin Chim Acta. 2009;400:97–102.

    Article  PubMed  CAS  Google Scholar 

  39. Motoyama K, Inoue H, Mimori K, Tanaka F, Kojima K, Uetake H, et al. Clinicopathological and prognostic significance of PDCD4 and microRNA-21 in human gastric cancer. Int J Oncol. 2010;36:1089–95.

    PubMed  CAS  Google Scholar 

  40. Graham DY, Shiotani A. The time to eradicate gastric cancer is now. Gut. 2005;54:735–8.

    Article  PubMed  CAS  Google Scholar 

  41. Graham DY, Uemura N. Natural history of gastric cancer after Helicobacter pylori eradication in Japan: after endoscopic resection, after treatment of the general population, and naturally. Helicobacter. 2006;11:139–43.

    Article  PubMed  Google Scholar 

  42. Johnnidis JB, Harris MH, Wheeler RT, Stehling-Sun S, Lam MH, Kirak O, et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature. 2008;451:1125–9.

    Article  PubMed  CAS  Google Scholar 

  43. Fukao T, Fukuda Y, Kiga K, Sharif J, Hino K, Enomoto Y, et al. An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell. 2007;129:617–31.

    Article  PubMed  CAS  Google Scholar 

  44. Roush S, Slack FJ. The let-7 family of microRNAs. Trends Cell Biol. 2008;18:505–16.

    Article  PubMed  CAS  Google Scholar 

  45. Peter ME. Let-7 and miR-200 microRNAs: guardians against pluripotency and cancer progression. Cell Cycle. 2009;8:843–52.

    Article  PubMed  CAS  Google Scholar 

  46. Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T. MicroRNA expression profiling in prostate cancer. Cancer Res. 2007;67:6130–5.

    Article  PubMed  CAS  Google Scholar 

  47. Nakada C, Matsuura K, Tsukamoto Y, Tanigawa M, Yoshimoto T, Narimatsu T, et al. Genome-wide microRNA expression profiling in renal cell carcinoma: significant down-regulation of miR-141 and miR-200c. J Pathol. 2008;216:418–27.

    Article  PubMed  CAS  Google Scholar 

  48. Gramantieri L, Ferracin M, Fornari F, Veronese A, Sabbioni S, Liu CG, et al. Cyclin G1 is a target of miR-122a, a microRNA frequently down-regulated in human hepatocellular carcinoma. Cancer Res. 2007;67:6092–9.

    Article  PubMed  CAS  Google Scholar 

  49. Hu M, Xia M, Chen X, Lin Z, Xu Y, Ma Y, et al. MicroRNA-141 regulates Smad interacting protein 1 (SIP1) and inhibits migration and invasion of colorectal cancer cells. Dig Dis Sci. 2010;55:2365–72.

    Article  PubMed  CAS  Google Scholar 

  50. Iorio MV, Visone R, Di Leva G, Donati V, Petrocca F, Casalini P, et al. MicroRNA signatures in human ovarian cancer. Cancer Res. 2007;67:8699–707.

    Article  PubMed  CAS  Google Scholar 

  51. Bandres E, Cubedo E, Agirre X, Malumbres R, Zarate R, Ramirez N, et al. Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues. Mol Cancer. 2006;5:29–38.

    Article  PubMed  CAS  Google Scholar 

  52. Slaby O, Svoboda M, Fabian P, Smerdova T, Knoflickova D, Bednarikova M, et al. Altered expression of miR-21, miR-31, miR-143 and miR-145 is related to clinicopathologic features of colorectal cancer. Oncology. 2007;72:397–402.

    Article  PubMed  CAS  Google Scholar 

  53. Michael MZ, O’ Connor SM, van Holst Pellekaan NG, Young GP, James RJ. Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res. 2003;1:882–91.

    PubMed  CAS  Google Scholar 

  54. Dijckmeester WA, Wijnhoven BP, Watson DI, Leong MP, Michael MZ, Mayne GC, et al. MicroRNA-143 and -205 expression in neosquamous esophageal epithelium following Argon plasma ablation of Barrett’s esophagus. J Gastrointest Surg. 2009;13:846–53.

    Article  PubMed  Google Scholar 

  55. Ng EK, Tsang WP, Ng SS, Jin HC, Yu J, Li JJ, et al. MicroRNA-143 targets DNA methyltransferases 3A in colorectal cancer. Br J Cancer. 2009;101:699–706.

    Article  PubMed  CAS  Google Scholar 

  56. Krutzfeldt J, Rosch N, Hausser J, Manoharan M, Zavolan M, Stoffel M. MicroRNA-194 is a target of transcription factor 1 (Tcf1, Hnf1alpha) in adult liver and controls expression of frizzled-6. Hepatology. 2012;55:98–107.

    Article  PubMed  Google Scholar 

  57. Dong P, Kaneuchi M, Watari H, Hamada J, Sudo S, Ju J, et al. MicroRNA-194 inhibits epithelial to mesenchymal transition of endometrial cancer cells by targeting oncogene BMI-1. Mol Cancer. 2011;10:99–107.

    Article  PubMed  CAS  Google Scholar 

  58. Huang J, Zhao L, Xing L, Chen D. MicroRNA-204 regulates Runx2 protein expression and mesenchymal progenitor cell differentiation. Stem Cells. 2010;28:357–64.

    PubMed  Google Scholar 

  59. Wang FE, Zhang C, Maminishkis A, Dong L, Zhi C, Li R, et al. MicroRNA-204/211 alters epithelial physiology. FASEB J. 2010;24:1552–71.

    Article  PubMed  CAS  Google Scholar 

  60. Yang Z, Chen S, Luan X, Li Y, Liu M, Li X, et al. MicroRNA-214 is aberrantly expressed in cervical cancers and inhibits the growth of HeLa cells. IUBMB Life. 2009;61:1075–82.

    Article  PubMed  CAS  Google Scholar 

  61. Li X, Zhang Y, Zhang H, Liu X, Gong T, Li M, et al. miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3. Mol Cancer Res. 2011;9:824–33.

    Article  PubMed  CAS  Google Scholar 

  62. Xu Y, Deng Y, Yan X, Zhou T. Targeting miR-375 in gastric cancer. Expert Opin Ther Targets. 2011;15:961–72.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors thank Professor David Y. Graham for helpful comments and Ms Maki Nomura for assistance with the laboratory work.

Conflict of interest

There is no conflict of interest and no funding sources including pharmaceutical and industry support.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Department of Internal Medicine, Kawasaki Medical School, 577 Matsushima, Kurashiki, Okayama, 701-0192, Japan

    Akiko Shiotani, Takahisa Murao, Tomoko Kanzaki, Yoshiki Kimura, Tomoari Kamada & Ken Haruma

  2. Department of Comprehensive Medicine, Kawasaki Medical School, Okayama, Japan

    Hiroaki Kusunoki & Kazuhiko Inoue

  3. Department of Gastrointestinal Oncology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

    Noriya Uedo & Hiroyasu Iishi

Authors
  1. Akiko Shiotani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Noriya Uedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hiroyasu Iishi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Takahisa Murao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tomoko Kanzaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoshiki Kimura
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tomoari Kamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Hiroaki Kusunoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Kazuhiko Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ken Haruma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Akiko Shiotani.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Shiotani, A., Uedo, N., Iishi, H. et al. H. pylori eradication did not improve dysregulation of specific oncogenic miRNAs in intestinal metaplastic glands. J Gastroenterol 47, 988–998 (2012). https://doi.org/10.1007/s00535-012-0562-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-012-0562-7

Keywords

Search

Navigation