MicroRNA‑23a/27a/24‑2 cluster promotes gastric cancer cell proliferation synergistically

Hua,Kate; Chen,Yu‑Ting; Chen,Chian‑Feng; Tang,Ya‑Syuan; Huang,Tzu‑Ting; Lin,Yu‑Cheng; Yeh,Tien‑Shun; Huang,Kuo‑Hung; Lee,Hsin‑Chen; Hsu,Ming‑Ta; Chi,Chin‑Wen; Wu,Chew‑Wun; Lin,Chi‑Hung; Ping,Yueh‑Hsin

doi:10.3892/ol.2018.8924

MicroRNA‑23a/27a/24‑2 cluster promotes gastric cancer cell proliferation synergistically

Authors:
- Kate Hua
- Yu‑Ting Chen
- Chian‑Feng Chen
- Ya‑Syuan Tang
- Tzu‑Ting Huang
- Yu‑Cheng Lin
- Tien‑Shun Yeh
- Kuo‑Hung Huang
- Hsin‑Chen Lee
- Ming‑Ta Hsu
- Chin‑Wen Chi
- Chew‑Wun Wu
- Chi‑Hung Lin
- Yueh‑Hsin Ping
View Affiliations

Affiliations: Department and Institute of Pharmacology, School of Medicine, National Yang‑Ming University, Taipei 11221, Taiwan, R.O.C., VYM Genome Research Center, School of Medicine, National Yang‑Ming University, Taipei 11221, Taiwan, R.O.C., Department of Surgery, Taipei Veterans General Hospital, Taipei 11221, Taiwan, R.O.C.
Published online on: June 7, 2018 https://doi.org/10.3892/ol.2018.8924
Pages: 2319-2325
Copyright: © Hua et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Previous studies have indicated that certain microRNAs (miRNAs/miRs) function as either tumor suppressors or oncogenes in human cancer. The present study identified the miR‑23a/27a/24‑2 cluster, containing miR‑23, miR‑27a and miR‑24, as an oncogene in gastric cancer. The expression of the miR‑23a/27a/24‑2 cluster was upregulated in clinical gastric cancer tissues. Transfection with inhibitors of miR‑23a, miR‑27a, or miR‑24, either independently or together, repressed in vitro colony formation and in vivo tumor formation. The miR23a/27a/24‑2 cluster inhibitors repressed the growth of gastric cancer cells in a synergistic manner. In addition, treatment with lower doses of the miRNA inhibitor mixture induced the formation of apoptotic bodies. According to computational predictions using TargetScan, suppressor of cytokine‑induced signaling 6 (SOCS6) was identified as one of the downstream target genes of the miR‑23a/27a/24‑2 cluster. The expression of SOCS6 was significantly lower in tumor tissues than in matched normal tissues (P<0.01) and was associated with poor survival (P<0.00001). Taken together, these results strongly suggested that the miR‑23a/27a/24‑2 cluster may mediate the progression of gastric cancer through the suppression of SOCS6 expression. The present study also provides a novel molecular target for the development of an anti‑gastric cancer agent.

View Figures

View References

1	Ang TL and Fock KM: Clinical epidemiology of gastric cancer. Singapore Med J. 55:621–628. 2014. View Article : Google Scholar : PubMed/NCBI
2	Wu CW, Lo SS, Shen KH, Hsieh MC, Chen JH, Chiang JH, Lin HJ, Li AF and Lui WY: Incidence and factors associated with recurrence patterns after intended curative surgery for gastric cancer. World J Surg. 27:153–158. 2003.PubMed/NCBI
3	Kim VN: MicroRNA biogenesis: Coordinated cropping and dicing. Nat Rev Mol Cell Biol. 6:376–385. 2005. View Article : Google Scholar : PubMed/NCBI
4	Bentwich I, Avniel A, Karov Y, Aharonov R, Gilad S, Barad O, Barzilai A, Einat P, Einav U, Meiri E, et al: Identification of hundreds of conserved and nonconserved human microRNAs. Nat Genet. 37:766–770. 2005. View Article : Google Scholar : PubMed/NCBI
5	Liang H and Li WH: Lowly expressed human microRNA genes evolve rapidly. Mol Biol Evol. 26:1195–1198. 2009. View Article : Google Scholar : PubMed/NCBI
6	Rodriguez A, Griffiths-Jones S, Ashurst JL and Bradley A: Identification of mammalian microRNA host genes and transcription units. Genome Res. 14:1902–1910. 2004. View Article : Google Scholar : PubMed/NCBI
7	Lee YS and Dutta A: MicroRNAs in cancer. Annu Rev Pathol. 4:199–227. 2009. View Article : Google Scholar : PubMed/NCBI
8	Zhu K, Liu D, Lai H, Li J and Wang C: Developing miRNA therapeutics for cardiac repair in ischemic heart disease. J Thorac Dis. 8:E918–E927. 2016. View Article : Google Scholar : PubMed/NCBI
9	Liang W, Gao S, Liang L, Huang X, Hu N, Lu X and Zhao Y: miRNA-34b is directly involved in the aging of macrophages. Aging Clin Exp Res. 29:599–607. 2017. View Article : Google Scholar : PubMed/NCBI
10	Shi C, Huang F, Gu X, Zhang M, Wen J, Wang X, You L, Cui X, Ji C and Guo X: Adipogenic miRNA and meta-signature miRNAs involved in human adipocyte differentiation and obesity. Oncotarget. 7:40830–40845. 2016.PubMed/NCBI
11	Petriv OI, Hansen CL, Humphries RK and Kuchenbauer F: Probing the complexity of miRNA expression across hematopoiesis. Cell Cycle. 10:2–3. 2011. View Article : Google Scholar : PubMed/NCBI
12	Hunter T: Cooperation between oncogenes. Cell. 64:249–270. 1991. View Article : Google Scholar : PubMed/NCBI
13	He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ and Hammond SM: A microRNA polycistron as a potential human oncogene. Nature. 435:828–833. 2005. View Article : Google Scholar : PubMed/NCBI
14	Yu Q, Yang X, Duan W, Li C, Luo Y and Lu S: miRNA-346 promotes proliferation, migration and invasion in liver cancer. Oncol Lett. 14:3255–3260. 2017. View Article : Google Scholar : PubMed/NCBI
15	Zhang Y, Wu YY, Jiang JN, Liu XS, Ji FJ and Fang XD: MiRNA-3978 regulates peritoneal gastric cancer metastasis by targeting legumain. Oncotarget. 7:83223–83230. 2016.PubMed/NCBI
16	Kumar MS, Lu J, Mercer KL, Golub TR and Jacks T: Impaired microRNA processing enhances cellular transformation and tumorigenesis. Nat Genet. 39:673–677. 2007. View Article : Google Scholar : PubMed/NCBI
17	Garzon R, Marcucci G and Croce CM: Targeting microRNAs in cancer: Rationale, strategies and challenges. Nat Rev Drug Discov. 9:775–789. 2010. View Article : Google Scholar : PubMed/NCBI
18	Song JH and Meltzer SJ: MicroRNAs in pathogenesis, diagnosis, and treatment of gastroesophageal cancers. Gastroenterology. 143:35–47, e2. 2012. View Article : Google Scholar : PubMed/NCBI
19	Su Z, Zhao J, Rong Z, Geng W and Wang Z: MiR-451, a potential prognostic biomarker and tumor suppressor for gastric cancer. Int J Clin Exp Pathol. 8:9154–9160. 2015.PubMed/NCBI
20	Du Y, Xu Y, Ding L, Yao H, Yu H, Zhou T and Si J: Down-regulation of miR-141 in gastric cancer and its involvement in cell growth. J Gastroenterol. 44:556–561. 2009. View Article : Google Scholar : PubMed/NCBI
21	Zhao X, Yang L and Hu J: Down-regulation of miR-27a might inhibit proliferation and drug resistance of gastric cancer cells. J Exp Clin Cancer Res. 30:552011. View Article : Google Scholar : PubMed/NCBI
22	Cao W, Fan R, Wang L, Cheng S, Li H, Jiang J, Geng M, Jin Y and Wu Y: Expression and regulatory function of miRNA-34a in targeting survivin in gastric cancer cells. Tumour Biol. 34:963–971. 2013. View Article : Google Scholar : PubMed/NCBI
23	Xia L, Zhang D, Du R, Pan Y, Zhao L, Sun S, Hong L, Liu J and Fan D: miR-15b and miR-16 modulate multidrug resistance by targeting BCL2 in human gastric cancer cells. Int J Cancer. 123:372–379. 2008. View Article : Google Scholar : PubMed/NCBI
24	Yang L, Liang H, Wang Y, Gao S, Yin K, Liu Z, Zheng X, Lv Y, Wang L, Zhang CY, et al: MiRNA-203 suppresses tumor cell proliferation, migration and invasion by targeting Slug in gastric cancer. Protein Cell. 7:383–387. 2016. View Article : Google Scholar : PubMed/NCBI
25	Zhang R, Li F, Wang W, Wang X, Li S and Liu J: The effect of antisense inhibitor of miRNA 106b~25 on the proliferation, invasion, migration, and apoptosis of gastric cancer cell. Tumour Biol. 37:10507–10515. 2016. View Article : Google Scholar : PubMed/NCBI
26	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
27	Kabir NN, Sun J, Ronnstrand L and Kazi JU: SOCS6 is a selective suppressor of receptor tyrosine kinase signaling. Tumour Biol. 35:10581–10589. 2014. View Article : Google Scholar : PubMed/NCBI
28	Szász AM, Lánczky A, Nagy A, Förster S, Hark K, Green JE, Boussioutas A, Busuttil R, Szabó A and Győrffy B: Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget. 7:49322–49333. 2016. View Article : Google Scholar : PubMed/NCBI
29	Abu-Elneel K, Liu T, Gazzaniga FS, Nishimura Y, Wall DP, Geschwind DH, Lao K and Kosik KS: Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetic. 9:153–161. 2008. View Article : Google Scholar
30	Sayed D, Hong C, Chen IY, Lypowy J and Abdellatif M: MicroRNAs play an essential role in the development of cardiac hypertrophy. Circ Res. 100:416–424. 2007. View Article : Google Scholar : PubMed/NCBI
31	van Rooij E, Sutherland LB, Liu N, Williams AH, McAnally J, Gerard RD, Richardson JA and Olson EN: A signature pattern of stress-responsive microRNAs that can evoke cardiac hypertrophy and heart failure. Proc Natl Acad Sci USA. 103:18255–18260. 2006. View Article : Google Scholar : PubMed/NCBI
32	Murakami Y, Yasuda T, Saigo K, Urashima T, Toyoda H, Okanoue T and Shimotohno K: Comprehensive analysis of microRNA expression patterns in hepatocellular carcinoma and non-tumorous tissues. Oncogene. 25:2537–2545. 2006. View Article : Google Scholar : PubMed/NCBI
33	Perkins DO, Jeffries CD, Jarskog LF, Thomson JM, Woods K, Newman MA, Parker JS, Jin J and Hammond SM: microRNA expression in the prefrontal cortex of individuals with schizophrenia and schizoaffective disorder. Genome Biol. 8:R272007. View Article : Google Scholar : PubMed/NCBI
34	Chhabra R, Dubey R and Saini N: Cooperative and individualistic functions of the microRNAs in the miR-23a~27a~24-2 cluster and its implication in human diseases. Mol Cancer. 9:2322010. View Article : Google Scholar : PubMed/NCBI
35	Xi Y, Shalgi R, Fodstad O, Pilpel Y and Ju J: Differentially regulated micro-RNAs and actively translated messenger RNA transcripts by tumor suppressor p53 in colon cancer. Clin Cancer Res. 12:2014–2024. 2006. View Article : Google Scholar : PubMed/NCBI
36	Ma S, Liu M, Xu Z, Li Y, Guo H, Ge Y, Liu Y, Zheng D and Shi J: A double feedback loop mediated by microRNA-23a/27a/24-2 regulates M1 versus M2 macrophage polarization and thus regulates cancer progression. Oncotarget. 7:13502–13519. 2016.PubMed/NCBI
37	Liu X, Ru J, Zhang J, Zhu LH, Liu M, Li X and Tang H: miR-23a targets interferon regulatory factor 1 and modulates cellular proliferation and paclitaxel-induced apoptosis in gastric adenocarcinoma cells. PLoS One. 8:e647072013. View Article : Google Scholar : PubMed/NCBI
38	Zhu LH, Liu T, Tang H, Tian RQ, Su C, Liu M and Li X: MicroRNA-23a promotes the growth of gastric adenocarcinoma cell line MGC803 and downregulates interleukin-6 receptor. FEBS J. 277:3726–3734. 2010. View Article : Google Scholar : PubMed/NCBI
39	Zhou L, Liang X, Zhang L, Yang L, Nagao N, Wu H, Liu C, Lin S, Cai G and Liu J: MiR-27a-3p functions as an oncogene in gastric cancer by targeting BTG2. Oncotarget. 7:51943–51954. 2016.PubMed/NCBI
40	Liu T, Tang H, Lang Y, Liu M and Li X: MicroRNA-27a functions as an oncogene in gastric adenocarcinoma by targeting prohibitin. Cancer Lett. 273:233–242. 2009. View Article : Google Scholar : PubMed/NCBI
41	Zhang H, Duan J, Qu Y, Deng T, Liu R, Zhang L, Bai M, Li J, Ning T, Ge S, et al: Onco-miR-24 regulates cell growth and apoptosis by targeting BCL2L11 in gastric cancer. Protein Cell. 7:141–151. 2016. View Article : Google Scholar : PubMed/NCBI
42	Yuan X, Liu C, Yang P, He S, Liao Q, Kang S and Zhao Y: Clustered microRNAs' coordination in regulating protein-protein interaction network. BMC Syst Biol. 3:652009. View Article : Google Scholar : PubMed/NCBI
43	Masuhara M, Sakamoto H, Matsumoto A, Suzuki R, Yasukawa H, Mitsui K, Wakioka T, Tanimura S, Sasaki A, Misawa H, et al: Cloning and characterization of novel CIS family genes. Biochem Biophys Res Commun. 239:439–446. 1997. View Article : Google Scholar : PubMed/NCBI
44	Lai RH, Hsiao YW, Wang MJ, Lin HY, Wu CW, Chi CW, Li AF, Jou YS and Chen JY: SOCS6, down-regulated in gastric cancer, inhibits cell proliferation and colony formation. Cancer Lett. 288:75–85. 2010. View Article : Google Scholar : PubMed/NCBI