title: MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor.
abstract: Metastasis is a major clinical obstacle in the treatment of gastric cancer (GC) and it accounts for the majority of cancer-related mortality. MicroRNAs have recently emerged as regulators of metastasis by acting on multiple signaling pathways. In this study, we found that miR-7 is significantly downregulated in highly metastatic GC cell lines and metastatic tissues. Both gain-of-function and loss-of-function experiments showed that increased miR-7 expression significantly reduced GC cell migration and invasion, whereas decreased miR-7 expression dramatically enhanced cell migration and invasion. In vivo metastasis assays also demonstrated that overexpression of miR-7 markedly inhibited GC metastasis. Moreover, the insulin-like growth factor-1 receptor (IGF1R) oncogene, which is often mutated or amplified in human cancers and functions as an important regulator of cell growth and tumor invasion, was identified as a direct target of miR-7. Silencing of IGF1R using small interefering RNA (siRNA) recapitulated the anti-metastatic function of miR-7, whereas restoring the IGF1R expression attenuated the function of miR-7 in GC cells. Furthermore, we found that suppression of Snail by miR-7, through targeting IGF1R, increased E-cadherin expression and partially reversed the epithelial-mesenchymal transition (EMT). Finally, analyses of miR-7 and IGF1R levels in human primary GC with matched lymph node metastasis tissue arrays revealed that miR-7 is inversely correlated with IGF1R expression. The present study provides insight into the specific biological behavior of miR-7 in EMT and tumor metastasis. Targeting this novel miR-7/IGF1R/Snail axis would be helpful as a therapeutic approach to block GC metastasis.
authors.affiliation: State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, The Fourth Military Medical University, Xi'an, China.
authors.forename: X
authors.initials: X
authors.lastname: Zhao
authors.forename: W
authors.initials: W
authors.lastname: Dou
authors.forename: L
authors.initials: L
authors.lastname: He
authors.forename: S
authors.initials: S
authors.lastname: Liang
authors.forename: J
authors.initials: J
authors.lastname: Tie
authors.forename: C
authors.initials: C
authors.lastname: Liu
authors.forename: T
authors.initials: T
authors.lastname: Li
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: P
authors.initials: P
authors.lastname: Mo
authors.forename: Y
authors.initials: Y
authors.lastname: Shi
authors.forename: K
authors.initials: K
authors.lastname: Wu
authors.forename: Y
authors.initials: Y
authors.lastname: Nie
authors.forename: D
authors.initials: D
authors.lastname: Fan
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D002478:Cells, Cultured; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018390:Gene Targeting; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D058990:Molecular Targeted Therapy; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs; D034741:RNA, Small Interfering; D017526:Receptor, IGF Type 1; C549242:MIRN7-1 microRNA, human