title: MicroRNA-375 inhibits tumour growth and metastasis in oesophageal squamous cell carcinoma through repressing insulin-like growth factor 1 receptor.
abstract: BACKGROUND
  To understand the involvement of micro-RNA (miRNA) in the development and progression of oesophageal squamous cell carcinoma (ESCC), miRNA profiles were compared between tumour and corresponding non-tumour tissues.
  
  
  METHODS
  miRCURY LNA array was used to generate miRNA expressing profile. Real-time quantitative PCR was applied to detectthe expression of miR-375 in ESCC samples and its correlation with insulin-like growth factor 1 receptor (IGF1R). Methylation-specific PCR was used to study the methylation status in the promoter region of miR-375. The tumour-suppressive effect of miR-375 was determined by both in-vitro and in-vivo assays.
  
  
  RESULTS
  The downregulation of miR-375 was frequently detected in primary ESCC, which was significantly correlated with advanced stage (p=0.003), distant metastasis (p<0.0001), poor overall survival (p=0.048) and disease-free survival (p=0.0006). Promoter methylation of miR-375 was detected in 26 of 45 (57.8%) ESCC specimens. Functional assays demonstrated that miR-375 could inhibit clonogenicity, cell motility, cell proliferation, tumour formation and metastasis in mice. Further study showed that miR-375 could interact with the 3'-untranslated region of IGF1R and downregulate its expression. In clinical specimens, the expression of IGF1R was also negatively correlated with miR-375 expression (p=0.008).
  
  
  CONCLUSIONS
  This study demonstrates that miR-375 has a strong tumour-suppressive effect through inhibiting the expression of IGF1R. The downregulation of miR-375, which is mainly caused by promoter methylation, is one of the molecular mechanisms involved in the development and progression of ESCC.
authors.affiliation: Department of Clinical Oncology, University of Hong Kong, Hong Kong, China.
authors.forename: Kar Lok
authors.initials: KL
authors.lastname: Kong
authors.forename: Dora Lai Wan
authors.initials: DL
authors.lastname: Kwong
authors.forename: Tim Hon-Man
authors.initials: TH
authors.lastname: Chan
authors.forename: Simon Ying-Kit
authors.initials: SY
authors.lastname: Law
authors.forename: Leilei
authors.initials: L
authors.lastname: Chen
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.forename: Yan-Ru
authors.initials: YR
authors.lastname: Qin
authors.forename: Xin-Yuan
authors.initials: XY
authors.lastname: Guan
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000737:chemistry / Q000378:metabolism*; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D018572:Disease-Free Survival; D015536:Down-Regulation; D004938:Esophageal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D008745:Methylation; D051379:Mice; D016513:Mice, SCID; D035683:MicroRNAs / Q000737:chemistry / Q000378:metabolism*; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D060888:Real-Time Polymerase Chain Reaction; D017526:Receptor, IGF Type 1 / Q000378:metabolism*; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; C540933:MIRN375 microRNA, human; D035683:MicroRNAs; D017526:Receptor, IGF Type 1