miR-126 functions as a tumour suppressor in human gastric cancer.

MicroRNAs have emerged as important gene regulators and are recognised as key players in carcinogenesis. In the present study, we show that miR-126 was significantly down-regulated in gastric cancer tissues compared with matched normal tissues and was associated with clinicopathological features, including tumour size, lymph node metastasis, local invasion and tumour-node-metastasis (TNM) stage. Ectopic expression of miR-126 in SGC-7901 gastric cancer cells potently inhibited cell growth by inducing cell cycle arrest in G0/G1 phase, migration and invasion in vitro as well as tumorigenicity and metastasis in vivo. Mechanistically, we identified the adaptor protein Crk as a target of miR-126. Taken together, our results suggest that miR-126 may function as a tumour suppressor in gastric cancer, with Crk as a direct target.

[1]  Tasneem Motiwala,et al.  Down-regulation of Micro-RNA-1 (miR-1) in Lung Cancer , 2008, Journal of Biological Chemistry.

[2]  R. Birge,et al.  Crk and CrkL adaptor proteins: networks for physiological and pathological signaling , 2009, Cell Communication and Signaling.

[3]  Y. Qu,et al.  In vitro and In vivo Evidence of Metallopanstimulin-1 in Gastric Cancer Progression and Tumorigenicity , 2006, Clinical Cancer Research.

[4]  Qiong Shao,et al.  MicroRNA miR-21 overexpression in human breast cancer is associated with advanced clinical stage, lymph node metastasis and patient poor prognosis. , 2008, RNA.

[5]  David E. Misek,et al.  Increased C-CRK proto-oncogene expression is associated with an aggressive phenotype in lung adenocarcinomas , 2003, Oncogene.

[6]  N. Mochizuki,et al.  Involvement of adaptor protein Crk in malignant feature of human ovarian cancer cell line MCAS , 2006, Oncogene.

[7]  B. Xiao,et al.  Down-regulation of miR-31 expression in gastric cancer tissues and its clinical significance , 2010, Medical oncology.

[8]  D. Iliopoulos,et al.  E2F1-regulated microRNAs impair TGFbeta-dependent cell-cycle arrest and apoptosis in gastric cancer. , 2008, Cancer cell.

[9]  F. Koohdani,et al.  Comparison of Ki-67 antigen expression and K-ras mutation in lung tumours induced by urethane in mice. , 2009, Singapore medical journal.

[10]  Bo Liu,et al.  MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo. , 2009, Lung cancer.

[11]  Xiaohua Li,et al.  Survival prediction of gastric cancer by a seven-microRNA signature , 2009, Gut.

[12]  Ming Yao,et al.  MicroRNA‐30d promotes tumor invasion and metastasis by targeting Galphai2 in hepatocellular carcinoma , 2010, Hepatology.

[13]  Tianhua Zhou,et al.  Down-regulation of miR-141 in gastric cancer and its involvement in cell growth , 2009, Journal of Gastroenterology.

[14]  Mauro Biffoni,et al.  The miR-15a–miR-16-1 cluster controls prostate cancer by targeting multiple oncogenic activities , 2008, Nature Medicine.

[15]  W. Gerald,et al.  Endogenous human microRNAs that suppress breast cancer metastasis , 2008, Nature.

[16]  Hong Lu,et al.  Reduced microRNA‐218 expression is associated with high nuclear factor kappa B activation in gastric cancer , 2009, Cancer.

[17]  C. Sasakawa,et al.  Interaction of CagA with Crk plays an important role in Helicobacter pylori–induced loss of gastric epithelial cell adhesion , 2005, The Journal of experimental medicine.

[18]  W. Filipowicz,et al.  Mechanisms of miRNA-mediated post-transcriptional regulation in animal cells. , 2009, Current opinion in cell biology.

[19]  A. Hatzigeorgiou,et al.  A guide through present computational approaches for the identification of mammalian microRNA targets , 2006, Nature Methods.

[20]  A. Tanigami,et al.  Molecular and immunohistochemical analysis of signaling adaptor protein Crk in human cancers. , 2002, Cancer letters.

[21]  Naoto Tsuchiya,et al.  Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells , 2007, Proceedings of the National Academy of Sciences.

[22]  S. Feller,et al.  Crk adaptor protein-induced phosphorylation of Gab1 on tyrosine 307 via Src is important for organization of focal adhesions and enhanced cell migration , 2009, Cell Research.

[23]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[24]  S. Zincirkeser,et al.  FDG PET-CT in cervical cancer: relationship between primary tumor FDG uptake and metastatic potential , 2010, Nuclear medicine communications.

[25]  G. Nuovo,et al.  MicroRNA-126 inhibits invasion in non-small cell lung carcinoma cell lines. , 2008, Biochemical and biophysical research communications.

[26]  V. Ambros.  The functions of animal microRNAs , 2004, Nature.

[27]  R. Weinberg,et al.  Tumour invasion and metastasis initiated by microRNA-10b in breast cancer , 2007, Nature.

[28]  Farin Kamangar,et al.  Patterns of cancer incidence, mortality, and prevalence across five continents: defining priorities to reduce cancer disparities in different geographic regions of the world. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  Huan Yang,et al.  MicroRNA expression profiling in human ovarian cancer: miR-214 induces cell survival and cisplatin resistance by targeting PTEN. , 2008, Cancer research.

[30]  J. Roh,et al.  Changing Patterns of Prognosticators During 15-Year Follow-Up of Advanced Gastric Cancer after Radical Gastrectomy and Adjuvant Chemotherapy: A 15-Year Follow-Up Study at a Single Korean Institute , 2007, Annals of Surgical Oncology.

[31]  Morag Park,et al.  CrkI and CrkII Function as Key Signaling Integrators for Migration and Invasion of Cancer Cells , 2005, Molecular Cancer Research.

[32]  M. Tsuda,et al.  Signaling adaptor protein Crk is indispensable for malignant feature of glioblastoma cell line KMG4. , 2007, Biochemical and biophysical research communications.

[33]  Rong Huan,et al.  Detection of miR-106a in gastric carcinoma and its clinical significance. , 2009, Clinica chimica acta; international journal of clinical chemistry.

[34]  Xianjun Wang,et al.  Detection of let-7a microRNA by real-time PCR in gastric carcinoma. , 2007, World journal of gastroenterology.

[35]  Jidong Liu,et al.  Control of protein synthesis and mRNA degradation by microRNAs. , 2008, Current opinion in cell biology.

[36]  Y. Akao,et al.  Decreased Expression of MicroRNA-143 and -145 in Human Gastric Cancers , 2009, Oncology.