MiR-214 regulate gastric cancer cell proliferation, migration and invasion by targeting PTEN

Cancer Cell International

Zhen-Shun Song¹  Bo Zhou¹  Yi-Ling Wang¹  Xu-Dong Wang¹  Xiao-Hu Yang¹  Ting-Song Yang¹ 

[1] Department of Hepato-Biliary-Pancreatic Surgery, Tenth Peoples’ Hospital, School of Medicine, Tongji University, 301 Middle Yanchang Road, Shanghai 200072, China

关键词: Invasion;    Proliferation;    Gastric cancer;    PTEN;    miR-214;   

Others  :  793433
DOI  :  10.1186/1475-2867-13-68

 received in 2013-02-05, accepted in 2013-07-01,  发布年份 2013

【 摘 要 】

Background

MicroRNAs are a class of small non-coding RNAs that play an important role in various human tumor initiation and progression by regulating gene expression negatively. The aim of this study was to investigate the effect of miR-214 on cell proliferation, migration and invasion, as well as the functional connection between miR-214 and PTEN in gastric cancer.

Methods

miR-214 and PTEN expression was determined in gastric cancer and matched normal tissues, and human gastric cancer cell lines by quantitative real-time PCR. The roles of miR-214 in cell proliferation, migration and invasion were analyzed with anti-miR-214 transfected cells. In addition, the regulation of PTEN by miR-214 was evaluated by Western blotting and luciferase reporter assays.

Results

miR-214 was noted to be highly overexpressed in gastric cancer tissues and cell lines using qRT-PCR. The expression level of miR-214 is significantly associated with clinical progression and poor prognosis according to the analysis of the clinicopathologic data. We also found that the miR-214 levels are inversely correlated with PTEN in tumor tissues. And PTEN expression level is also associated with metastasis and invasion of gastric cancer. In addition, knockdown of miR-214 could significantly inhibit proliferation, migration and invasion of gastric cancer cells. Moreover, we demonstrate that PTEN is regulated negatively by miR-214 through a miR-214 binding site within the 3’-UTR of PTEN at the posttranscriptional level in gastric cancer cells.

Conclusions

These findings indicated that miR-214 regulated the proliferation, migration and invasion by targeting PTEN post-transcriptionally in gastric cancer. It may be a novel potential therapeutic agent for gastric cancer.

【 授权许可】

   
2013 Yang et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics, 2011. CA Cancer J Clin 2011, 61:69-90.
• [2]Brenner H, Rothenbacher D, Arndt V: Epidemiology of stomach cancer. Methods Mol Biol 2009, 472:467-477.
• [3]Tamura G: Alterations of tumor suppressor and tumor related genes in the development and progression of gastric cancer. World J Gastroenterol 2006, 12:192-198.
• [4]Valencia-Sanchez MA, Liu J, Hannon GJ, Parker R: Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 2006, 20:515-524.
• [5]Hobert O: Gene regulation by transcription factors and microRNAs. Science 2008, 319:1785-1786.
• [6]Ahmed FE: Role of miRNA in carcinogenesis and biomarker selection: a methodological view. Expert Rev Mol Diagn 2007, 7:569-603.
• [7]Meng F, Henson R, Wehbe-Janek H, Ghoshal K, Jacob ST, Patel T: MicroRNA-21 regulates expression of the PTEN tumor suppressor gene in human hepatocellular cancer. Gastroenterology 2007, 133:647-658.
• [8]Hiyoshi Y, Kamohara H, Karashima R, Sato N, Imamura Y, Nagai Y, Yoshida N, Toyama E, Hayashi N, Watanabe M, Baba H: MicroRNA-21 regulates the proliferation and invasion in esophageal squamous cell carcinoma. Clin Cancer Res 2009, 15:1915-1922.
• [9]Moriyama T, Ohuchida K, Mizumoto K, Yu J, Sato N, Nabae T, Takahata S, Toma H, Nagai E, Tanaka M: MicroRNA-21 modulates biological functions of pancreatic cancer cells including their proliferation, invasion, and chemoresistance. Mol Cancer Ther 2009, 8:1067-1074.
• [10]Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, Alder H, Liu CG, Oue N, Yasui W, Yoshida K, Sasaki H, Nomura S, Seto Y, Kaminishi M, Calin GA, Croce CM: Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol 2010, 11:136-146.
• [11]Yuan Y, Zeng ZY, Liu XH, Gong DJ, Tao J, Cheng HZ, Huang SD: MicroRNA-203 inhibits cell proliferation by repressing ΔNp63 expression in human esophageal squamous cell carcinoma. BMC Cancer 2011, 11:57. BioMed Central Full Text
• [12]Tang H, Tang XY, Liu M, Li X: Targeting alpha-fetoprotein represses the proliferation of hepatoma cells via regulation of the cell cycle. Clin ChimActa 2008, 394:81-88.
• [13]Yang H, Kong W, He L, Zhao JJ, O'Donnell JD, Wang J, Wenham RM, Coppola D, Kruk PA, Nicosia SV, Cheng JQ: MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. Cancer Res 2008, 68:425-433.
• [14]He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, Powers S, Cordon-Cardo C, Lowe SW, Hannon GJ, Hammond SM: A microRNA polycistron as a potential human oncogene. Nature 2005, 435:828-833.
• [15]Volinia S, Calin GA, Liu CG, Ambs S, Cimmino A, Petrocca F, Visone R, Iorio M, Roldo C, Ferracin M, Prueitt RL, Yanaihara N, Lanza G, Scarpa A, Vecchione A, Negrini M, Harris CC, Croce CM: A microRNA expression signature of human solid tumors defines cancer gene targets. Proc Natl Acad Sci USA 2006, 103:2257-2261.
• [16]Esquela-Kerscher A, Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer 2006, 6:259-269.
• [17]Maes OC, An J, Sarojini H, Wang E: Murine microRNAs implicated in liver functions and aging process. Mech Ageing Dev 2008, 129:534-541.
• [18]Flynt AS, Li N, Thatcher EJ, Solnica-Krezel L, Patton JG: Zebrafish miR-214 modulates Hedgehog signaling to specify muscle cell fate. Nat Genet 2007, 39:259-263.
• [19]Zhang XJ, Ye H, Zeng CW, He B, Zhang H, Chen YQ: Dysregulation of miR-15a and miR-214 in human pancreatic cancer. J Hematol Oncol 2010, 3:46. BioMed Central Full Text
• [20]Yang Z, Chen S, Luan X, Li Y, Liu M, Li X, Liu T, Tang H: MicroRNA-214 is aberrantly expressed in cervical cancers and inhibits the growth of HeLa cells. IUBMB Life 2009, 61:1075-1082.
• [21]Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, Parsons R: PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science 1997, 275:1943-1947.
• [22]Leslie NR, Bennett D, Lindsay YE, Stewart H, Gray A, Downes CP: Redox regulation of PI3-kinase signalling via inactivation of PTEN. EMBO J 2003, 22:5501-5510.
• [23]Stewart AL, Mhashilkar AM, Yang XH, Ekmekcioglu S, Saito Y, Sieger K, Schrock R, Onishi E, Swanson X, Mumm JB, Zumstein L, Watson GJ, Snary D, Roth JA, Grimm EA, Ramesh R, Chada S: PI3K blockade by Ad-PTEN inhibits invasion and induces apoptosis in radial growth phase and metastatic melanoma cells. Mol Med 2002, 8:451-461.
• [24]Tamura M, Gu J, Matsumoto K, Aota S, Parsons R, Yamada KM: Inhibition of cell migration, spreading, and focal adhesions by tumor suppressor PTEN. Science 1998, 280:1614-1617.
• [25]Castellino RC, Durden DL: Mechanisms of disease: the PI3K-Akt-PTEN signaling node-an intercept point for the control of angiogenesis in brain tumors. Nat Clin Pract Neurol 2007, 3:682-693.
• [26]Yang L, Kuang LG, Zheng HC, Li JY, Wu DY, Zhang SM, Xin Y: PTEN encoding product: a marker for tumorigenesis and progression of gastric carcinoma. World J Gastroenterol 2003, 1:35-39.
• [27]Zheng HC, Li YL, Sun JM, Yang XF, Li XH, Jiang WG, Zhang YC, Xin Y: Growth, invasion, metastasis, differentiation, angiogenesis and apoptosis of gastric cancer regulated by expression of PTEN encoding products. World J Gastroenterol 2003, 9:1662-1666.