title: Tumor suppressor role of miR-133a in gastric cancer by repressing IGF1R.
abstract: OBJECTIVE
  To investigate the function and mechanism of miR-133a in gastric cancer (GC) and its relationship with clinicopathological characteristics of GC.
  
  
  METHODS
  A total of 105 GC patients who underwent surgical resection as primary treatment were selected for this study. Real-time quantitative reverse transcriptase polymerase chain (qRT-PCR) was used to examine the expression levels of miR-133a in human GC and adjacent non-tumor tissues, as well as in GC cell lines (SGC-7901, BGC-823, MGC-803, and AGS) and a human gastric mucosal epithelial cell line (GES-1). The biological role of miRNA (miR)-133a was assessed in the GC cell lines using MTT, apoptosis, migration and invasion, and colony formation assays, and xenograft tumorigenesis. qRT-PCR and western blot analyses were used to evaluate the potential target gene expression of miR-133a. Pearson's correlation was calculated to evaluate the correlation between miR-133a and insulin-like growth factor 1 receptor (IGF1R) expression. The regulation of IGF1R by miR-133a was verified using the luciferase reporter assay.
  
  
  RESULTS
  In 80% of the 105 GC patients, the mean expression of miR-133a was significantly downregulated in tumor tissues compared with adjacent normal tissues (1.215 ± 0.1477 vs 3.093 ± 0.4104, P < 0.0001). Downregulation of miR-133a was significantly correlated with the degree of differentiation (P = 0.01), local invasion (P = 0.001) and TNM stage (P = 0.02) in GC patients. Compared with a control construct, forced expression of miR-133a in GC cell lines inhibited proliferation (0.4787 ± 0.0219 vs 0.7050 ± 0.0147, P = 0.0013 in SGC-7901 cells; and 0.5448 ± 0.0085 vs 0.7270 ± 0.0084, P = 0.001 in MGC-803 cells); migration (0.6333 ± 0.0233 vs 1.037 ± 0.0584, P = 0.003 in SGC-7901 cells; 0.6126 ± 0.0311 vs 1.024 ± 0.0456, P = 0.0017 in MGC-803 cells); and invasion (0.613 ± 0.0399 vs 1.033 ± 0.0278, P = 0.0013 in SGC-7901 cells; 0.7433 ± 0.0221 vs 1.017 ± 0.0311, P = 0.002 in MGC-803 cells). It also induced apoptosis (18.19% ± 0.2483% vs 5.887% ± 0.3837%, P < 0.0001 in SGC-7901 cells; 22.69% ± 0.7846% vs 9.347% ± 0.3012%, P < 0.0001 in MGC-803 cells). Furthermore, miR-133a inhibited tumor growth and xenograft tumorigenesis of SGC -7901 cells in vivo. In addition, we identified IGF1R as a regulatory target of miR-133a in GC.
  
  
  CONCLUSIONS
  This study suggests that miR-133a is downregulated in GC and functions as a tumor suppressor in vitro and in vivo partly by repressing IGF1R.
authors.affiliation: Yu Gong, Jun Ren, Kun Liu, Li-Ming Tang, Department of Gastrointestinal Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou 213000, Jiangsu Province, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Gong
authors.affiliation: Yu Gong, Jun Ren, Kun Liu, Li-Ming Tang, Department of Gastrointestinal Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou 213000, Jiangsu Province, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ren
authors.affiliation: Yu Gong, Jun Ren, Kun Liu, Li-Ming Tang, Department of Gastrointestinal Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou 213000, Jiangsu Province, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Liu
authors.affiliation: Yu Gong, Jun Ren, Kun Liu, Li-Ming Tang, Department of Gastrointestinal Surgery, Nanjing Medical University Affiliated Changzhou No. 2 People's Hospital, Changzhou 213000, Jiangsu Province, China.
authors.forename: Li-Ming
authors.initials: LM
authors.lastname: Tang
mesh_terms: D000818:Animals; D017209:Apoptosis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy / Q000379:methods; D006801:Humans; D008297:Male; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D017526:Receptor, IGF Type 1; D017451:Receptors, Somatomedin / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D013997:Time Factors; D014162:Transfection; D047368:Tumor Burden; D023041:Xenograft Model Antitumor Assays
chemical_list: C000597236:IGF1R protein, human; C548234:MIRN133 microRNA, human; D035683:MicroRNAs; D017451:Receptors, Somatomedin; D017526:Receptor, IGF Type 1
keywords: Gastric cancer; Insulin-like growth factor 1 receptor; Tumor suppressor; miR-133a