Long non‑coding RNA H19 regulates cell growth and metastasis via the miR‑22‑3p/Snail1 axis in gastric cancer

Gan,Li; Lv,Lin; Liao,Shengtao

doi:10.3892/ijo.2019.4773

Long non‑coding RNA H19 regulates cell growth and metastasis via the miR‑22‑3p/Snail1 axis in gastric cancer

Authors:
- Li Gan
- Lin Lv
- Shengtao Liao
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Affiliations: Department of Anatomy, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China, Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
Published online on: April 4, 2019 https://doi.org/10.3892/ijo.2019.4773
Pages: 2157-2168

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Abstract

Gastric cancer (GC) is the fifth most prevalent type of malignancy and the third leading cause of cancer‑related mortality worldwide, with the prognosis of patients with late‑stage GC remaining at poor levels. Long non‑coding RNA (lncRNA) H19 (H19) is involved in the growth and metastasis of tumors, and it is upregulated under hypoxic conditions and in certain types of cancer; however, the underlying mechanisms of action of this lncRNA as regards the initiation and development of GC remain unknown. Thus, in the present study, we aimed to determine the role of lncRNA H19 in GC and to elucidate the underlying mechanisms. H19 was found to be upregulated in GC tissues and cells compared with the para‑cancerous tissues, and an elevated expression of H19 was associated with lymph node metastasis and TNM stage. Furthermore, the downregulation of H19 suppressed the proliferation, invasion, migration and epithelial‑mesenchymal transition of GC cells in vitro and suppressed tumor growth in vivo. H19 was also found to be able to bind with miR‑22‑3p, and H19‑induced cell growth and metastasis were shown to be reversed by the upregulation of miR‑22‑3p; the miR‑22‑3p level was found to inversely correlate with H19 expression in GC tissues. Furthermore, the overexpression of miR‑22‑3p notably suppressed the proliferation, migration and invasion of GC cells, and these effects were enhanced by the downregulation of Snail1. In addition, cell growth and metastasis induced by miR‑22‑3p downregulation were partially reversed by the knockdown of Snail1. Furthermore, a negative correlation was observed between the mRNA expression levels of miR‑22‑3p and Snail1 in GC tissues. On the whole, the findings of the present study revealed that H19 was upregulated in GC tissues, which promoted tumor growth and metastasis via the miR‑22‑3p/Snail1 signaling pathway. In summary, these findings provide novel insight into the potential regulatory roles of H19 in GC, and suggest that the H19/miR‑22‑3p/Snail1 axis may prove to be a promising therapeutic target for the treatment of patients with GC.

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1	Graham DY: Helicobacter pylori update: Gastric cancer, reliable therapy, and possible benefits. Gastroenterology. 148:719–31. e32015. View Article : Google Scholar : PubMed/NCBI
2	Hamashima C, Shabana M, Okada K, Okamoto M and Osaki Y: Mortality reduction from gastric cancer by endoscopic and radio-graphic screening. Cancer Sci. 106:1744–1749. 2015. View Article : Google Scholar : PubMed/NCBI
3	Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, Bannon F, Ahn JV, Johnson CJ, Bonaventure A, et al CONCORD Working Group: Global surveillance of cancer survival 1995-2009: Analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 385:977–1010. 2015. View Article : Google Scholar
4	Oliveira C, Pinheiro H, Figueiredo J, Seruca R and Carneiro F: Familial gastric cancer: Genetic susceptibility, pathology, and implications for management. Lancet Oncol. 16:e60–e70. 2015. View Article : Google Scholar : PubMed/NCBI
5	Garajová I, Ferracin M, Porcellini E, Palloni A, Abbati F, Biasco G and Brandi G: Non-coding RNAs as predictive biomarkers to current treatment in metastatic colorectal cancer. Int J Mol Sci. 18:15472017. View Article : Google Scholar :
6	Pop-Bica C, Gulei D, Cojocneanu-Petric R, Braicu C, Petrut B and Berindan-Neagoe I: Understanding the role of non-coding RNAs in bladder cancer: From dark matter to valuable therapeutic targets. Int J Mol Sci. 18:15142017. View Article : Google Scholar :
7	Hao NB, He YF, Li XQ, Wang K and Wang RL: The role of miRNA and lncRNA in gastric cancer. Oncotarget. 8:81572–81582. 2017. View Article : Google Scholar : PubMed/NCBI
8	Chandra S, Vimal D, Sharma D, Rai V, Gupta SC and Chowdhuri DK: Role of miRNAs in development and disease: Lessons learnt from small organisms. Life Sci. 185:8–14. 2017. View Article : Google Scholar : PubMed/NCBI
9	Zhan JW, Jiao DM, Wang Y, Song J, Wu JH, Wu LJ, Chen QY and Ma SL: Integrated microRNA and gene expression profiling reveals the crucial miRNAs in curcumin anti-lung cancer cell invasion. Thorac Cancer. 8:461–470. 2017. View Article : Google Scholar : PubMed/NCBI
10	Liang WC, Ren JL, Wong CW, Chan SO, Waye MM, Fu WM and Zhang JF: lncRNA-NEF antagonized epithelial to mesenchymal transition and cancer metastasis via cis-regulating FOXA2 and inactivating Wnt/β-catenin signaling. Oncogene. 37:1445–1456. 2018. View Article : Google Scholar : PubMed/NCBI
11	Chen Y, Huang W, Sun W, Zheng B, Wang C, Luo Z, Wang J and Yan W: lncRNA MALAT1 promotes cancer metastasis in osteosarcoma via activation of the PI3K-Akt signaling pathway. Cell Physiol Biochem. 51:1313–1326. 2018. View Article : Google Scholar : PubMed/NCBI
12	Chen G, Cao Y, Zhang L, Ma H, Shen C and Zhao J: Analysis of long non-coding RNA expression profiles identifies novel lncRNA biomarkers in the tumorigenesis and malignant progression of gliomas. Oncotarget. 8:67744–67753. 2017.PubMed/NCBI
13	Cao MX, Jiang YP, Tang YL and Liang XH: The crosstalk between lncRNA and microRNA in cancer metastasis: Orchestrating the epithelial-mesenchymal plasticity. Oncotarget. 8:12472–12483. 2017.
14	Li P, Tong L, Song Y, Sun J, Shi J, Wu Z, Diao Y, Li Y and Wang Z: Long noncoding RNA H19 participates in metformin-mediated inhibition of gastric cancer cell invasion. J Cell Physiol. 234:4515–4527. 2019. View Article : Google Scholar
15	Collette J, Le Bourhis X and Adriaenssens E: Regulation of human breast cancer by the long non-coding RNA H19. Int J Mol Sci. 18:23192017. View Article : Google Scholar :
16	Huang Z, Lei W, Hu HB, Zhang H and Zhu Y: H19 promotes non-small-cell lung cancer (NSCLC) development through STAT3 signaling via sponging miR-17. J Cell Physiol. 233:6768–6776. 2018. View Article : Google Scholar : PubMed/NCBI
17	Li CF, Li YC, Wang Y and Sun LB: The effect of lncRNA H19/miR-194-5p axis on the epithelial-mesenchymal transition of colorectal adenocarcinoma. Cell Physiol Biochem. 50:196–213. 2018. View Article : Google Scholar : PubMed/NCBI
18	Zhuang M, Gao W, Xu J, Wang P and Shu Y: The long non-coding RNA H19-derived miR-675 modulates human gastric cancer cell proliferation by targeting tumor suppressor RUNX1. Biochem Biophys Res Commun. 448:315–322. 2014. View Article : Google Scholar : PubMed/NCBI
19	Jafarzadeh-Samani Z, Sohrabi S, Shirmohammadi K, Effatpanah H, Yadegarazari R and Saidijam M: Evaluation of miR-22 and miR-20a as diagnostic biomarkers for gastric cancer. Linchuang Zhongliuxue Zazhi. 6:162017.
20	Li B, Li B, Sun H and Zhang H: The predicted target gene validation, function, and prognosis studies of miRNA-22 in colorectal cancer tissue. Tumour Biol. 39:10104283176922572017.PubMed/NCBI
21	Chen J, Wu FX, Luo HL, Liu JJ, Luo T, Bai T, Li LQ and Fan XH: Berberine upregulates miR-22-3p to suppress hepatocellular carcinoma cell proliferation by targeting Sp1. Am J Transl Res. 8:4932–4941. 2016.PubMed/NCBI
22	Lv KT, Liu Z, Feng J, Zhao W, Hao T, Ding WY, Chu JP and Gao LJ: miR-22-3p regulates cell proliferation and inhibits cell apoptosis through targeting the eIF4EBP3 gene in human cervical squamous carcinoma cells. Int J Med Sci. 15:142–152. 2018. View Article : Google Scholar : PubMed/NCBI
23	Xin M, Qiao Z, Li J, Liu J, Song S, Zhao X, Miao P, Tang T, Wang L, Liu W, et al: miR-22 inhibits tumor growth and metastasis by targeting ATP citrate lyase: Evidence in osteo-sarcoma, prostate cancer, cervical cancer and lung cancer. Oncotarget. 7:44252–44265. 2016. View Article : Google Scholar : PubMed/NCBI
24	Wang X, Zou M, Li J, Wang B, Zhang Q, Liu F and Lü G: lncRNA H19 targets miR-22 to modulate H₂O₂-induced deregulation in nucleus pulposus cell senescence, proliferation, and ECM synthesis through Wnt signaling. J Cell Biochem. 119:4990–5002. 2018. View Article : Google Scholar : PubMed/NCBI
25	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2 (-∆ ∆ C (T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar
26	Gooding AJ, Zhang B, Jahanbani FK, Gilmore HL, Chang JC, Valadkhan S and Schiemann WP: The lncRNA BORG drives breast cancer metastasis and disease recurrence. Sci Rep. 7:126982017. View Article : Google Scholar : PubMed/NCBI
27	Wu H, Hu Y, Liu X, Song W, Gong P, Zhang K, Chen Z, Zhou M, Shen X, Qian Y, et al: lncRNA TRERNA1 function as an enhancer of SNAI1 promotes gastric cancer metastasis by regulating epithelial-mesenchymal transition. Mol Ther Nucleic Acids. 8:291–299. 2017. View Article : Google Scholar : PubMed/NCBI
28	Zhao L, Han T, Li Y, Sun J, Zhang S, Liu Y, Shan B, Zheng D and Shi J: The lncRNA SNHG5/miR-32 axis regulates gastric cancer cell proliferation and migration by targeting KLF4. FASEB J. 31:893–903. 2017. View Article : Google Scholar
29	Lü MH, Tang B, Zeng S, Hu CJ, Xie R, Wu YY, Wang SM, He FT and Yang SM: Long noncoding RNA BC032469, a novel competing endogenous RNA, upregulates hTERT expression by sponging miR-1207-5p and promotes proliferation in gastric cancer. Oncogene. 35:3524–3534. 2016. View Article : Google Scholar
30	Xu TP, Liu XX, Xia R, Yin L, Kong R, Chen WM, Huang MD and Shu YQ: SP1-induced upregulation of the long noncoding RNA TINCR regulates cell proliferation and apoptosis by affecting KLF2 mRNA stability in gastric cancer. Oncogene. 34:5648–5661. 2015. View Article : Google Scholar : PubMed/NCBI
31	Yan J, Zhang Y, She Q, Li X, Peng L, Wang X, Liu S, Shen X, Zhang W, Dong Y, et al: Long Noncoding RNA H19/miR-675 axis promotes gastric cancer via FADD/caspase 8/caspase 3 signaling pathway. Cell Physiol Biochem. 42:2364–2376. 2017. View Article : Google Scholar : PubMed/NCBI
32	Liu G, Xiang T, Wu QF and Wang WX: Long noncoding RNA H19-derived miR-675 enhances proliferation and invasion via RUNX1 in gastric cancer cells. Oncol Res. 23:99–107. 2016. View Article : Google Scholar : PubMed/NCBI
33	Hu Q, Yin J, Zeng A, Jin X, Zhang Z, Yan W and You Y: H19 functions as a competing endogenous RNA to regulate EMT by sponging miR-130a-3p in glioma. Cell Physiol Biochem. 50:233–245. 2018. View Article : Google Scholar : PubMed/NCBI
34	Vennin C, Spruyt N, Dahmani F, Julien S, Bertucci F, Finetti P, Chassat T, Bourette RP, Le Bourhis X and Adriaenssens E: H19 non coding RNA-derived miR-675 enhances tumorigenesis and metastasis of breast cancer cells by downregulating c-Cbl and Cbl-b. Oncotarget. 6:29209–29223. 2015. View Article : Google Scholar : PubMed/NCBI
35	Hu J, Huang Y, Wu Y, Liu F, Sun D, Wang K and Qu H: NTRK2 is an oncogene and associated with microRNA-22 regulation in human gastric cancer cell lines. Tumour Biol. 37:15115–15123. 2016. View Article : Google Scholar : PubMed/NCBI
36	Zuo QF, Cao LY, Yu T, Gong L, Wang LN, Zhao YL, Xiao B and Zou QM: MicroRNA-22 inhibits tumor growth and metastasis in gastric cancer by directly targeting MMP14 and Snail. Cell Death Dis. 6:e20002015. View Article : Google Scholar : PubMed/NCBI
37	Zhou LH, Yang YC, Zhang RY, Wang P, Pang MH and Liang LQ: CircRNA_0023642 promotes migration and invasion of gastric cancer cells by regulating EMT. Eur Rev Med Pharmacol Sci. 22:2297–2303. 2018.PubMed/NCBI
38	Xiang Z, Jiang DP, Xia GG, Wei ZW, Chen W, He Y and Zhang CH: CXCL1 expression is correlated with Snail expression and affects the prognosis of patients with gastric cancer. Oncol Lett. 10:2458–2464. 2015. View Article : Google Scholar : PubMed/NCBI
39	Zhao J, Yang C, Guo S and Wu Y: GM130 regulates epithelial- to-mesenchymal transition and invasion of gastric cancer cells via snail. Int J Clin Exp Pathol. 8:10784–10791. 2015.
40	Zhang J, Zhou Y and Yang Y: CCR7 pathway induces epithelial-mesenchymal transition through up-regulation of Snail signaling in gastric cancer. Med Oncol. 32:4672015.PubMed/NCBI
41	Feng Y, Sun T, Yu Y, Gao Y, Wang X and Chen Z: MicroRNA-370 inhibits the proliferation, invasion and EMT of gastric cancer cells by directly targeting PAQR4. J Pharmacol Sci. 138:96–106. 2018. View Article : Google Scholar : PubMed/NCBI