title: The molecular mechanism of microRNA-145 to suppress invasion-metastasis cascade in gastric cancer.
abstract: Invasion and metastasis are the major features of malignant tumors that are responsible for 90% of cancer-related deaths. Recently, microRNAs have been discovered to have a role in suppressing tumor metastasis. This study's aim was to clarify the roles of miR-145 in gastric carcinomas and its underlying molecular mechanism in regulating tumor metastasis. Here, we demonstrate a stepwise downregulation of miR-145 level in nontumorous gastric mucosa, primary gastric cancers and their secondary metastases. In vitro analysis of miR-145's ectopic expression and loss-of-function suggests that it suppresses gastric cancer cell migration and invasion. In vivo spontaneous metastasis and experimental metastasis assay further confirm its function in suppressing the invasion-metastasis cascade, including impairing local invasion and inhibiting hematogenous metastasis in gastric cancers. Furthermore, we identified a novel mechanism of miR-145 to suppress metastasis. N-cadherin (CDH2) was proved to be a direct target of miR-145, using luciferase assay and western blot. Re-expressing N-cadherin in miR-145-transfected cells reverses their migration and invasion defects. Although not a direct target of miR-145, matrix metallopeptidase 9 (MMP9), but not MMP2, was also significantly decreased in miR-145-expressing cells. We suggest that miR-145 suppresses tumor metastasis by inhibiting N-cadherin protein translation, and then indirectly downregulates its downstream effector MMP9.
authors.affiliation: Department of Pathology, Qilu Hospital, Shandong University, Shandong, PR China. gaopeng@sdu.edu.cn
authors.forename: P
authors.initials: P
authors.lastname: Gao
authors.forename: A-Y
authors.initials: AY
authors.lastname: Xing
authors.forename: G-Y
authors.initials: GY
authors.lastname: Zhou
authors.forename: T-G
authors.initials: TG
authors.lastname: Zhang
authors.forename: J-P
authors.initials: JP
authors.lastname: Zhang
authors.forename: C
authors.initials: C
authors.lastname: Gao
authors.forename: H
authors.initials: H
authors.lastname: Li
authors.forename: D-B
authors.initials: DB
authors.lastname: Shi
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D015536:Down-Regulation; D005753:Gastric Mucosa / Q000378:metabolism / Q000473:pathology; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*
chemical_list: D015703:Antigens, CD; C050361:CDH2 protein, human; D015820:Cadherins; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9