Transcriptome analysis of miRNA–lncRNA–mRNA interactions in the malignant transformation process of gastric cancer initiation

Article metrics

Abstract

Gastric cancer is a common heterogeneous malignancy that is pathologically characterized by the development of chronic atrophic gastritis and dysplasia of the epithelium. The pathogenic mechanisms at the molecular level are completely unclear. In the present study, we first address the expression network and miRNA–lncRNA–mRNA interaction in the malignant transformation process from normal mucosa and atrophic gastritis to a tumor. First, the long non-coding RNA (lncRNA), micro RNA (miRNA) and messenger RNA (mRNA) expression profiles of normal gastric mucosa, atrophic gastritis, gastric cancer and the peri-tumor tissues were analyzed using microarrays. Then, bioinformatic analyses were used to predict the gene targets and analyse their potential roles in tumorigenesis and progression of gastric cancer. Finally, an intersection analysis of microarray data showed that 10 miRNAs and 11 lncRNAs were detected in the malignant transformation process from normal mucosa tissues and atrophic gastritis to tumorigenesis, and many miRNAs and lncRNAs were novel and had important roles. Meanwhile, the significant pathways and biological functions regulated by the deregulated 21 non-coding genes were enriched. In conclusion, our work provides an important theoretical, experimental and clinical foundation for further research on more effective targets for the diagnosis, therapy and prognosis of gastric cancer.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1
Figure 2
Figure 3
Figure 4

References

  1. 1

    Arnold M, Karim-Kos HE, Coebergh JW, Byrnes G, Antilla A, Ferlay J et al. Recent trends in incidence of five common cancers in 26 European countries since 1988: analysis of the European Cancer Observatory. Eur J Cancer 2015; 51: 1164–1187.

  2. 2

    Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F et al. Cancer statistics in China, 2015. Cancer J Clin 2016; 66: 115–132.

  3. 3

    Siegel RL, Miller KD, Jemal A . Cancer statistics, 2016. Cancer J Clin 2016; 66: 7–30.

  4. 4

    Luebeck EG, Curtius K, Jeon J, Hazelton WD . Impact of tumor progression on cancer incidence curves. Cancer Res 2013; 73: 1086–1096.

  5. 5

    Li J, Deng Z, Wang Z, Wang D, Zhang L, Su Q et al. Zipper-interacting protein kinase promotes epithelial-mesenchymal transition, invasion and metastasis through AKT and NF-kB signaling and is associated with metastasis and poor prognosis in gastric cancer patients. Oncotarget 2015; 6: 8323–8338.

  6. 6

    Xiang M, Birkbak NJ, Vafaizadeh V, Walker SR, Yeh JE, Liu S et al. STAT3 induction of miR-146b forms a feedback loop to inhibit the NF-kappaB to IL-6 signaling axis and STAT3-driven cancer phenotypes. Sci Signal 2014; 7: ra11.

  7. 7

    Tsujimoto H, Ono S, Ichikura T, Matsumoto Y, Yamamoto J, Hase K . Roles of inflammatory cytokines in the progression of gastric cancer: friends or foes? Gastric Cancer 2010; 13: 212–221.

  8. 8

    Ooi WF, Xing M, Xu C, Yao X, Ramlee MK, Lim MC et al. Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity. Nat Commun 2016; 7: 12983.

  9. 9

    Zhang X, Peng Y, Jin Z, Huang W, Cheng Y, Liu Y et al. Integrated miRNA profiling and bioinformatics analyses reveal potential causative miRNAs in gastric adenocarcinoma. Oncotarget 2015; 6: 32878–32889.

  10. 10

    Alexander RP, Fang G, Rozowsky J, Snyder M, Gerstein MB . Annotating non-coding regions of the genome. Nat Rev Genet 2010; 11: 559–571.

  11. 11

    Bartel DP . MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116: 281–297.

  12. 12

    Guttman M, Rinn JL . Modular regulatory principles of large non-coding RNAs. Nature 2012; 482: 339–346.

  13. 13

    Wan X, Ding X, Chen S, Song H, Jiang H, Fang Y et al. The functional sites of miRNAs and lncRNAs in gastric carcinogenesis. Tumour Biol 2015; 36: 521–532.

  14. 14

    Gong J, Li J, Wang Y, Liu C, Jia H, Jiang C et al. Characterization of microRNA-29 family expression and investigation of their mechanistic roles in gastric cancer. Carcinogenesis 2014; 35: 497–506.

  15. 15

    Kogo R, Shimamura T, Mimori K, Kawahara K, Imoto S, Sudo T et al. Long noncoding RNA HOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers. Cancer Res 2011; 71: 6320–6326.

  16. 16

    Hu Y, Wang J, Qian J, Kong X, Tang J, Wang Y et al. Long noncoding RNA GAPLINC regulates CD44-dependent cell invasiveness and associates with poor prognosis of gastric cancer. Cancer Res 2014; 74: 6890–6902.

  17. 17

    Lauren P . The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 1965; 64: 31–49.

  18. 18

    Correa P . Human gastric carcinogenesis: a multistep and multifactorial process—First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52: 6735–6740.

  19. 19

    Xu Q, Wu YF, Li Y, He CY, Sun LP, Liu JW et al. SNP-SNP interactions of three new pri-miRNAs with the target gene PGC and multidimensional analysis of H. pylori in the gastric cancer/atrophic gastritis risk in a Chinese population. Oncotarget 2016; 7: 23700–23714.

  20. 20

    Kupcinskas J, Wex T, Link A, Leja M, Bruzaite I, Steponaitiene R et al. Gene polymorphisms of micrornas in Helicobacter pylori-induced high risk atrophic gastritis and gastric cancer. PloS One 2014; 9: e87467.

  21. 21

    Riquelme I, Tapia O, Leal P, Sandoval A, Varga MG, Letelier P et al. miR-101-2, miR-125b-2 and miR-451a act as potential tumor suppressors in gastric cancer through regulation of the PI3K/AKT/mTOR pathway. Cell Oncol 2016; 39: 23–33.

  22. 22

    Li H, Yu B, Li J, Su L, Yan M, Zhu Z et al. Overexpression of lncRNA H19 enhances carcinogenesis and metastasis of gastric cancer. Oncotarget 2014; 5: 2318–2329.

  23. 23

    Jin X, Yu N . MicroRNA-421 gene polymorphism in gastric carcinoma. Med Sci Monit 2016; 22: 1467–1471.

  24. 24

    Xia T, Liao Q, Jiang X, Shao Y, Xiao B, Xi Y et al. Long noncoding RNA associated-competing endogenous RNAs in gastric cancer. Sci Rep 2014; 4: 6088.

  25. 25

    Yuen ST, Leung SY . Genomics study of gastric cancer and its molecular subtypes. Adv Exp Med Biol 2016; 908: 419–439.

  26. 26

    Bibi F, Naseer MI, Alvi SA, Yasir M, Jiman-Fatani AA, Sawan A et al. microRNA analysis of gastric cancer patients from Saudi Arabian population. BMC Genomics 2016; 17: 751.

  27. 27

    Fan ZY, Liu W, Yan C, Zhu ZL, Xu W, Li JF et al. Identification of a five-lncRNA signature for the diagnosis and prognosis of gastric cancer. Tumour Biol 2016; 37: 13265–13277.

  28. 28

    Chen JS, Wang YF, Zhang XQ, Lv JM, Li Y, Liu XX et al. H19 serves as a diagnostic biomarker and up-regulation of H19 expression contributes to poor prognosis in patients with gastric cancer. Neoplasma 2016; 63: 223–230.

  29. 29

    Ge X, Liu X, Lin F, Li P, Liu K, Geng R et al. MicroRNA-421 regulated by HIF-1alpha promotes metastasis, inhibits apoptosis, and induces cisplatin resistance by targeting E-cadherin and caspase-3 in gastric cancer. Oncotarget 2016; 7: 24466–24482.

  30. 30

    Ponjavic J, Oliver PL, Lunter G, Ponting CP . Genomic and transcriptional co-localization of protein-coding and long non-coding RNA pairs in the developing brain. PLoS Genet 2009; 5: e1000617.

  31. 31

    Carninci P, Kasukawa T, Katayama S, Gough J, Frith MC, Maeda N et al. The transcriptional landscape of the mammalian genome. Science 2005; 309: 1559–1563.

  32. 32

    Goldenring JR, Nomura S . Differentiation of the gastric mucosa III. Animal models of oxyntic atrophy and metaplasia. Am J Physiol 2006; 291: G999–1004.

  33. 33

    Khan SA, Amnekar R, Khade B, Barreto SG, Ramadwar M, Shrikhande SV et al. p38-MAPK/MSK1-mediated overexpression of histone H3 serine 10 phosphorylation defines distance-dependent prognostic value of negative resection margin in gastric cancer. Clin Epigenet 2016; 8: 88.

  34. 34

    Zhao J, Sun BK, Erwin JA, Song JJ, Lee JT . Polycomb proteins targeted by a short repeat RNA to the mouse X chromosome. Science 2008; 322: 750–756.

  35. 35

    Li L, Liu B, Wapinski OL, Tsai MC, Qu K, Zhang J et al. Targeted disruption of Hotair leads to homeotic transformation and gene derepression. Cell Rep 2013; 5: 3–12.

  36. 36

    Yang L, Lin C, Jin C, Yang JC, Tanasa B, Li W et al. lncRNA-dependent mechanisms of androgen-receptor-regulated gene activation programs. Nature 2013; 500: 598–602.

  37. 37

    Trimarchi T, Bilal E, Ntziachristos P, Fabbri G, Dalla-Favera R, Tsirigos A et al. Genome-wide mapping and characterization of Notch-regulated long noncoding RNAs in acute leukemia. Cell 2014; 158: 593–606.

  38. 38

    Wang L, Zhao Y, Bao X, Zhu X, Kwok YK, Sun K et al. LncRNA Dum interacts with Dnmts to regulate Dppa2 expression during myogenic differentiation and muscle regeneration. Cell Res 2015; 25: 335–350.

  39. 39

    Zhao L, Han T, Li Y, Sun J, Zhang S, Liu Y et al. The lncRNA SNHG5/miR-32 axis regulates gastric cancer cell proliferation and migration by targeting KLF4. FASEB J 2016; 31: 893–903.

  40. 40

    Shao Y, Ye M, Li Q, Sun W, Ye G, Zhang X et al. LncRNA-RMRP promotes carcinogenesis by acting as a miR-206 sponge and is used as a novel biomarker for gastric cancer. Oncotarget 2016; 7: 37812–37824.

Download references

Acknowledgements

The work was supported by the New Century Excellent Talents in University, Ministry of Education of China, to Wang H; the Wanjiang Scholars Program of Anhui Province of China to Wang H; the Public Welfare Technology Application Research Linkage Project of Anhui Province of China, 1604f0804018 to Ding XP.

Author information

Correspondence to X Ding or H Wang.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Further reading