MicroRNA as a Molecular Marker for Predicting the Risk of Intestinal Type Gastric Cancer Development

The aim of the study was to assess expression of microRNAs (miRNAs) influencing the key carcinogenesis pathways in the tissues of gastric mucosa in patients with Н. pylori-associated chronic gastritis and gastric cancer of intestinal type (directly in the tumor tissue and mucosa of the stomach with morphological signs of chronic gastritis).

Materials and Methods. Objects of investigations were fragments of gastric mucosa of the antral part of the stomach with Н. pylori- associated chronic gastritis: 10 were bioptates with minimal changes, 9 bioplates with chronic gastritis, and specimens of surgical material taken from the stomachs with gastric cancer of intestinal type: 28 were tumor fragments and 22 the tissue from the sites beyond tumor growth (chronic atrophic gastritis). The number of miRNAs miR-146а, miR-155, miR-21, miR-223, miR-192, miR-200b, miR-221, miR-375 in paraffin sections was determined by a real-time semi-quantitative hairpin RT-PCR assay.

Results. The analysis of miR-21 and miR-223 showed the most statistically significant results among the investigated miRNAs. The expression level of oncogenic miR-21 and miR-223 significantly and successively increases in the range of the examined diseases from Н. pylori-associated chronic gastritis to intestinal type gastric adenocarcinoma.

Conclusion. MiRNAs miR-21 and miR-223 may be considered as perspective biomarkers for assessing the risk of development, early diagnosis, and prognosis of intestinal type gastric cancer.

1. Merabishvili V.M. Analytical epidemiology of gastric cancer. Voprosy onkologii 2013; 59(5): 565–570.
2. Rugge М., Genta R.M., Graham D.Y., Mario F., Coelho L.G., Kim N., Malfertheiner P., Sugano K., Tsukanov V., Correa P. Chronicles of a cancer foretold: 35 years of gastric cancer risk assessment. Gut 2016; 65(5): 721–725, https://doi.org/10.1136/gutjnl-2015-310846.
3. Fletcher C.D.M. Diagnostic histopathology of tumors. Philadelphia: Elsevier; 2013. 2296 p.
4. Haneklaus M., Gerlic M., O’Neill L.A., Masters S.L. miR-223: infection, inflammation and cancer. J Intern Med 2013; 274(3): 215–226, https://doi.org/10.1111/joim.12099.
5. Zhang Z., Li Z., Gao C., Chen P., Chen J., Liu W., Xiao S., Lu H. miR-21 plays a pivotal role in gastric cancer pathogenesis and progression. Lab Invest 2008; 88(12): 1358–1366, https://doi.org/10.1038/labinvest.2008.94.
6. Farazi T.A., Hoell J.I., Morozov P., Tuschl T. MicroRNAs in human cancer. Adv Exp Med Biol 2013; 774: 1–20, https://doi.org/10.1007/978-94-007-5590-1_1.
7. Nikitina E.G., Urazova L.N., Stegny V.N. MicroRNAs and human cancer. Exp Oncol 2012; 34(1): 2–8.
8. Esquela-Kerscher A., Slack F.J. Oncomirs — microRNAs with a role in cancer. Nat Rev Cancer 2006; 6(4): 259–269, https://doi.org/10.1038/nrc1840.
9. Shrestha S., Hsu S.D., Huang W.Y., Huang H.Y., Chen W., Weng S.L., Huang H.D. A systematic review of microRNA expression profiling studies in human gastric cancer. Cancer Med 2014; 3(4): 878–888, https://doi.org/10.1002/cam4.246.
10. Feng Y., Wang L., Zeng J., Shen L., Liang X., Yu H., Liu S., Liu Z., Sun Y., Li W., Chen C., Jia J. FoxM1 is overexpressed in Helicobacter pylori-induced gastric carcinogenesis and is negatively regulated by miR-370. Mol Cancer Res 2013, 11(8): 834–844, https://doi.org/10.1158/1541-7786.mcr-13-0007.
11. Zhu Y., Jiang Q., Lou X., Ji X., Wen Z., Wu J., Tao H., Jiang T., He W., Wang C., Du Q., Zheng S., Mao J., Huang J. MicroRNAs up-regulated by CagA of Helicobacter pylori induce intestinal metaplasia of gastric epithelial cells. PLoS One 2012, 7(4): e35147, https://doi.org/10.1371/journal.pone.0035147.
12. Liu X., Ru J., Zhang J., Zhu L.H., Liu M., Li X., Tang H. miR-23a targets interferon regulatory factor 1 and modulates cellular proliferation and paclitaxel-induced apoptosis in gastric adenocarcinoma cells. PLoS One 2013, 8(6): e64707, https://doi.org/10.1371/journal.pone.0064707.
13. Cadamuro A.C.T., Rossi A.F.T., Maniezzo N.M., Silva A.E. Helicobacter pylori infection: host immune response, implications on gene expression and microRNAs. World J Gastroenterol 2014; 20(6): 1424–1437, https://doi.org/10.3748/wjg.v20.i6.1424.
14. Ding S.Z., Goldberg J.B., Hatakeyama M. Helicobacter pylori infection, oncogenic pathways and epigenetic mechanisms in gastric carcinogenesis. Future Oncol 2010; 6(5): 851–862, https://doi.org/10.2217/fon.10.37.
15. Libânio D., Dinis-Ribeiro M., Pimentel-Nunes P. Helicobacter pylori and microRNAs: relation with innate immunity and progression of preneoplastic conditions. World J Clin Oncol 2015; 6(5): 111–132, https://doi.org/10.5306/wjco.v6.i5.111.
16. Wan X., Ding X., Chen S., Song H., Jiang H., Fang Y., Li P., Guo J. The functional sites of miRNAs and lncRNAs in gastric carcinogenesis. Tumour Biol 2015; 36(2): 521–532, https://doi.org/10.1007/s13277-015-3136-5.
17. Zhang B.G., Li J.F., Yu B.Q., Zhu Z.G., Liu B.Y., Yan M. microRNA-21 promotes tumor proliferation and invasion in gastric cancer by targeting PTEN. Oncol Rep 2012; 27(4): 1019–1026, https://doi.org/10.3892/or.2012.1645.
18. Li X., Zhang Y., Zhang H., Liu X., Gong T., Li M., Sun L., Ji G., Shi Y., Han Z., Han S., Nie Y., Chen X., Zhao Q., Ding J., Wu K., Daiming F. miRNA-223 promotes gastric cancer invasion and metastasis by targeting tumor suppressor EPB41L3. Mol Cancer Res 2011; 9(7): 824–833, https://doi.org/10.1158/1541-7786.mcr-10-0529.
19. Miao L., Liu K., Xie M., Xing Y., Xi T. miR-375 inhibits Helicobacter pylori-induced gastric carcinogenesis by blocking JAK2-STAT3 signaling. Cancer Immunol Immunother 2014; 63(7): 699–711, https://doi.org/10.1007/s00262-014-1550-y.

Rubtsov V.А., Fedotova Y.А., Ivanov M.K., Titov S.E., Pomorgailo E.G. MicroRNA as a Molecular Marker for Predicting the Risk of Intestinal Type Gastric Cancer Development. Sovremennye tehnologii v medicine 2018; 10(2): 151, https://doi.org/10.17691/stm2018.10.2.18