title: miR-194 suppresses metastasis of non-small cell lung cancer through regulating expression of BMP1 and p27(kip1).
abstract: MicroRNAs (miRNAs) are increasingly implicated in regulating tumor malignance through their capacity to coordinately repress expression of tumor-related genes. Here, we show that overexpression of miR-194 in lung cancer cell lines, results in suppressing metastasis of lung cancer cells, while inhibiting its expression through 'miRNA sponge' promotes the cancer cells to metastasize. miR-194 expression is also found to be in strongly negative association with metastasis in clinical specimens of non-small cell lung cancer. We demonstrate that miR-194 directly targets both BMP1 and p27(kip1). The resulting downregulation of BMP1 leads to suppression of TGFβ activity and, thus, to downregulation of the expression of key oncogenic genes (matrix metalloproteinases MMP2 and MMP9). This leads, in turn, to decreased tumor invasion. In addition, the miRNA-194-induced suppression of p27(kip1) activates the RhoA pathway, producing enhanced development of actin stress fibers and impaired migration of cancer cells. These findings reveal two structurally independent but functionally linked branches of the regulatory and signaling pathway that together provide a bridge between the metastasis-depressing miRNA and the key genes that govern the malignancy of lung cancers.
authors.affiliation: The State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Wu
authors.affiliation: The State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.affiliation: The State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: O
authors.initials: O
authors.lastname: Fang
authors.affiliation: School of Biosciences, The University of Birmingham, Birmingham, UK.
authors.forename: L J
authors.initials: LJ
authors.lastname: Leach
authors.affiliation: The State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China.
authors.forename: X
authors.initials: X
authors.lastname: Hu
authors.affiliation: 1] The State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai, China [2] School of Biosciences, The University of Birmingham, Birmingham, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Luo
mesh_terms: D001483:Base Sequence; D055395:Bone Morphogenetic Protein 1 / Q000235:genetics*; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D035683:MicroRNAs / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000235:genetics*
chemical_list: C554846:MIRN194 microRNA, human; D035683:MicroRNAs; D050760:Cyclin-Dependent Kinase Inhibitor p27; C525705:BMP1 protein, human; D055395:Bone Morphogenetic Protein 1