Identification and characterization of tumor suppressor and oncogenic miRNAs in gastric cancer

Chen,Zhaofeng; Liu,Xiaoguang; Hu,Zenan; Wang,Yuping; Liu,Min; Liu,Xiaojun; Li,Hailong; Ji,Rui; Guo,Qinhong; Zhou,Yongning

doi:10.3892/ol.2015.3179

Identification and characterization of tumor suppressor and oncogenic miRNAs in gastric cancer

Authors:
- Zhaofeng Chen
- Xiaoguang Liu
- Zenan Hu
- Yuping Wang
- Min Liu
- Xiaojun Liu
- Hailong Li
- Rui Ji
- Qinhong Guo
- Yongning Zhou
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Affiliations: Division of Gastroenterology and Hepatology, The First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P.R. China, Key Laboratory for Gastrointestinal Diseases of Gansu, Lanzhou University, Lanzhou, Gansu 730000, P.R. China
Published online on: May 6, 2015 https://doi.org/10.3892/ol.2015.3179
Pages: 329-336

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Abstract

The aim of the present study was to screen for and identify microRNAs (miRNAs/miRs) that are associated with gastric cancer and to clarify the role of these miRNAs in gastric cancer. Thus, the differential expression of a panel of miRNAs in two pairs of gastric cancer tissues and their matched adjacent healthy tissues was investigated by performing a microarray analysis. To verify the results of this screen, 56 gastric cancer tissues were analyzed for the selected miRNAs using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR). The association between the expression of a specific miRNA and the clinical data relating to the tissue samples [including age, gender, tumor size, tumor node metastasis (TNM) stage and lymph‑node metastasis] were subsequently examined. A total of 31 differentially expressed miRNAs were identified in the miRNA array. Using RT‑qPCR to verify these results, it was determined that 10 miRNAs exhibited high mRNA expression levels and 13 miRNAs exhibited a low expression in the gastric cancer tissue samples, while 8 miRNAs did not demonstrate an association with gastric cancer. Thus, the microarray and RT‑qPCR results demonstrated 74.2% (23/31 miRNAs) agreement. The association between the 23 miRNAs and the clinicopathological characteristics of the gastric cancer samples was investigated. It was identified that the expression levels of miR‑551b‑3p, miR‑133b, miR‑100‑5p and miR‑363‑3p were significantly downregulated in the gastric cancer tissues, and this downregulation was closely correlated with the degree of differentiation (i.e., tumor grade), TNM stage and lymph‑node metastasis (P<0.05). By contrast, the expression of miR‑215 was significantly upregulated in the gastric cancer tissues, and its expression level was correlated with tumor differentiation, TNM stage and lymph‑node metastasis (P<0.05). Furthermore, miR‑200a‑3p was upregulated in the gastric cancer tissues and its expression was significantly more prevalent in male patients compared with female patients (P<0.05). miR‑429 was upregulated in the gastric cancer tissues and its expression was significantly higher in patients who were >50 years of age (P<0.05). These data indicate that a number of these miRNAs may be important in the development of gastric cancer. In particular, miR‑551b‑3p, miR‑133b, miR‑100‑5p and miR‑363‑3p may act as tumor suppressors in the development of gastric cancer. By contrast, miR‑215 appears to exhibit oncogenic properties and promote the development of gastric cancer. In addition, the abnormal expression of miR‑200a‑3p may be associated with gender, while the abnormal expression of miR‑429 may be associated with age in patients with gastric cancer. However, additional studies are required to delineate the underlying mechanisms of the association, and to explore their potential as valid biomarkers in the diagnosis, classification and prognosis of gastric cancer.

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1	Jemal A, Bray F, Center MM, et al: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
2	Treiber T, Treiber N and Meister G: Regulation of microRNA biogenesis and function. Thromb Haemost. 107:605–610. 2012. View Article : Google Scholar : PubMed/NCBI
3	Anglicheau D, Muthukumar T and Suthanthiran M: MicroRNAs: small RNAs with big effects. Transplantation. 90:105–112. 2010. View Article : Google Scholar : PubMed/NCBI
4	Farazi TA, Hoell JI, Morozov P and Tuschl T: MicroRNAs in human cancer. Adv Exp Med Biol. 774:1–20. 2013.PubMed/NCBI
5	Mitchell PS, Parkin RK, Kroh EM, et al: Circulating microRNAs as stable blood-based markers for cancer detection. In: Proc Natl Acad Sci USA. 105. pp. 10513–10518. 2008; View Article : Google Scholar : PubMed/NCBI
6	Ng EK, Chong WW, Jin H, et al: Differential expression of microRNAs in plasma of patients with colorectal cancer: a potential marker for colorectal cancer screening. Gut. 58:1375–1381. 2009. View Article : Google Scholar : PubMed/NCBI
7	Wang HJ, Ruan HJ, He XJ, et al: MicroRNA-101 is down-regulated in gastric cancer and involved in cell migration and invasion. Eur J Cancer. 46:2295–2303. 2010. View Article : Google Scholar : PubMed/NCBI
8	Yao Y, Suo AL, Li ZF, et al: MicroRNA profiling of human gastric cancer. Mol Med Rep. 2:963–970. 2009.PubMed/NCBI
9	Ambros V: MicroRNA pathways in flies and worms: growth, death, fat, stress and timing. Cell. 113:673–676. 2003. View Article : Google Scholar : PubMed/NCBI
10	Rachagani S, Kumar S and Batra SK: MicroRNA in pancreatic cancer: pathological, diagnostic and therapeutic implications. Cancer Lett. 292:8–16. 2010. View Article : Google Scholar : PubMed/NCBI
11	Liu R, Zhang C, Hu Z, et al: A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis. Eur J Cancer. 47:784–791. 2011. View Article : Google Scholar : PubMed/NCBI
12	Xiong Y, Fang JH, Yun JP, et al: Effects of MicroRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology. 51:836–845. 2010.PubMed/NCBI
13	Synnergren J, Améen C, Lindahl A, et al: Expression of microRNAs and their target mRNAs in human stem cell-derived cardiomyocyte clusters and in heart tissue. Physiol Genomics. 43:581–594. 2011. View Article : Google Scholar : PubMed/NCBI
14	Calin GA and Croce CM: MicroRNA signatures in human cancers. Nat Rev Cancer. 6:857–866. 2006. View Article : Google Scholar : PubMed/NCBI
15	Lovat F, Valeri N and Croce CM: MicroRNAs in the pathogenesis of cancer. Semin Oncol. 38:724–733. 2011. View Article : Google Scholar : PubMed/NCBI
16	Simon R: Challenges of microarray data and the evaluation of gene expression profile signatures. Cancer Invest. 26:327–332. 2008. View Article : Google Scholar : PubMed/NCBI
17	Li Z, Cao Y, Jie Z, et al: miR-495 and miR-551a inhibit the migration and invasion of human gastric cancer cells by directly interacting with PRL-3. Cancer Lett. 323:41–47. 2012. View Article : Google Scholar : PubMed/NCBI
18	Yin VP, Lepilina A, Smith A and Poss KD: Regulation of zebrafish heart regeneration by miR-133. Dev Biol. 365:319–327. 2012. View Article : Google Scholar : PubMed/NCBI
19	Chen JF, Mandel EM, Thomson JM, et al: The role of microRNA-1 and microRNA-133 in skeletal muscle proliferation and differentiation. Nat Genet. 38:228–233. 2006. View Article : Google Scholar : PubMed/NCBI
20	Zhou Y, Wu D, Tao J, et al: MicroRNA-133 inhibits cell proliferation, migration and invasion by targeting epidermal growth factor receptor and its downstream effector proteins in bladder cancer. Scand J Urol. 47:423–432. 2013. View Article : Google Scholar : PubMed/NCBI
21	Tao J, Wu D, Xu B, et al: MicroRNA-133 inhibits cell proliferation, migration and invasion in prostate cancer cells by targeting the epidermal growth factor receptor. Oncol Rep. 27:1967–1975. 2012.PubMed/NCBI
22	Kinoshita T, Nohata N, Watanabe-Takano H, et al: Actin-related protein 2/3 complex subunit 5 (ARPC5) contributes to cell migration and invasion and is directly regulated by tumor-suppressive microRNA-133a in head and neck squamous cell carcinoma. Int J Oncol. 40:1770–1778. 2012.PubMed/NCBI
23	Moriya Y, Nohata N, Kinoshita T, et al: Tumor suppressive microRNA-133a regulates novel molecular networks in lung squamous cell carcinoma. J Hum Genet. 57:38–45. 2012. View Article : Google Scholar : PubMed/NCBI
24	Kawakami K, Enokida H, Chiyomaru T, et al: The functional significance of miR-1 and miR-133a in renal cell carcinoma. Eur J Cancer. 48:827–836. 2012. View Article : Google Scholar : PubMed/NCBI
25	Wu ZS, Wang CQ, Xiang R, et al: Loss of miR-133a expression associated with poor survival of breast cancer and restoration of miR-133a expression inhibited breast cancer cell growth and invasion. BMC Cancer. 12:512012. View Article : Google Scholar : PubMed/NCBI
26	Liu J, Lu KH, Liu ZL, et al: MicroRNA-100 is a potential molecular marker of non-small cell lung cancer and functions as a tumor suppressor by targeting polo-like kinase 1. BMC Cancer. 12:5192012. View Article : Google Scholar : PubMed/NCBI
27	Li BH, Zhou JS, Ye F, et al: Reduced miR-100 expression in cervical cancer and precursors and its carcinogenic effect through targeting PLK1 protein. Eur J Cancer. 47:2166–2174. 2011. View Article : Google Scholar : PubMed/NCBI
28	Peng DX, Luo M, Qiu LW, et al: Prognostic implications of microRNA-100 and its functional roles in human epithelial ovarian cancer. Oncol Rep. 27:1238–1244. 2012.PubMed/NCBI
29	Zheng YS, Zhang H, Zhang XJ, et al: MiR-100 regulates cell differentiation and survival by targeting RBSP3, a phosphatase-like tumor suppressor in acute myeloid leukemia. Oncogene. 31:80–92. 2012. View Article : Google Scholar : PubMed/NCBI
30	Sun Q, Zhang J, Cao W, et al: Dysregulated miR-363 affects head and neck cancer invasion and metastasis by targeting podoplanin. Int J Biochem Cell Biol. 45:513–520. 2013. View Article : Google Scholar : PubMed/NCBI
31	Georgieva B, Milev I, Minkov I, et al: Characterization of the uterine leiomyoma microRNAome by deep sequencing. Genomics. 99:275–281. 2012. View Article : Google Scholar : PubMed/NCBI
32	Georges SA, Biery MC, Kim SY, et al: Coordinated regulation of cell cycle transcripts by p53-Inducible microRNAs, miR-192 and miR-215. Cancer Res. 68:10105–10112. 2008. View Article : Google Scholar : PubMed/NCBI
33	Song B, Wang Y, Titmus MA, et al: Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells. Mol Cancer. 9:962010. View Article : Google Scholar : PubMed/NCBI
34	Boni V, Bitarte N, Cristobal I, et al: miR-192/miR-215 influence 5-fluorouracil resistance through cell cycle-mediated mechanisms complementary to its post-transcriptional thymidilate synthase regulation. Mol Cancer Ther. 9:2265–2275. 2010. View Article : Google Scholar : PubMed/NCBI
35	Wijnhoven BP, Hussey DJ, Watson DI, et al: South Australian Oesophageal Research Group: MicroRNA profiling of Barrett's oesophagus and oesophageal adenocarcinoma. Br J Surg. 97:853–861. 2010. View Article : Google Scholar : PubMed/NCBI
36	White NM, Khella HW, Grigull J, et al: miRNA profiling in metastatic renal cell carcinoma reveals a tumour-suppressor effect for miR-215. Br J Cancer. 105:1741–1749. 2011. View Article : Google Scholar : PubMed/NCBI
37	Faltejskova P, Svoboda M, Srutova K, et al: Identification and functional screening of microRNAs highly deregulated in colorectal cancer. J Cell Mol Med. 16:2655–2666. 2012. View Article : Google Scholar : PubMed/NCBI
38	Jin Z, Selaru FM, Cheng Y, et al: MicroRNA-192 and −215 are upregulated in human gastric cancer in vivo and suppress ALCAM expression in vitro. Oncogene. 30:1577–1585. 2011. View Article : Google Scholar : PubMed/NCBI
39	Ueda T, Volinia S, Okumura H, et al: Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol. 11:136–146. 2010. View Article : Google Scholar : PubMed/NCBI
40	Tsukamoto Y, Nakada C, Noguchi T, Tanigawa M, et al: MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. Cancer Res. 70:2339–2349. 2010. View Article : Google Scholar : PubMed/NCBI