title: MicroRNA-182 targets SMAD7 to potentiate TGFβ-induced epithelial-mesenchymal transition and metastasis of cancer cells.
abstract: The transforming growth factor β (TGFβ) pathway plays critical roles during cancer cell epithelial-mesenchymal transition (EMT) and metastasis. SMAD7 is both a transcriptional target and a negative regulator of TGFβ signalling, thus mediating a negative feedback loop that may potentially restrain TGFβ responses of cancer cells. Here, however, we show that TGFβ treatment induces SMAD7 transcription but not its protein level in a panel of cancer cells. Mechanistic studies reveal that TGFβ activates the expression of microRNA-182 (miR-182), which suppresses SMAD7 protein. miR-182 silencing leads to SMAD7 upregulation on TGFβ treatment and prevents TGFβ-induced EMT and invasion of cancer cells. Overexpression of miR-182 promotes breast tumour invasion and TGFβ-induced osteoclastogenesis for bone metastasis. Furthermore, miR-182 expression inversely correlates with SMAD7 protein in human tumour samples. Therefore, our data reveal the miR-182-mediated disruption of TGFβ self-restraint and provide a mechanism to explain the unleashed TGFβ responses in metastatic cancer cells.
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jingyi
authors.initials: J
authors.lastname: Yu
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Rong
authors.initials: R
authors.lastname: Lei
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xueqian
authors.initials: X
authors.lastname: Zhuang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xiaoxun
authors.initials: X
authors.lastname: Li
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.affiliation: Molecular Cell Biology Department, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Sima
authors.initials: S
authors.lastname: Lev
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, New York 10016, USA.
authors.forename: Miguel F
authors.identifier: 0000-0003-0916-3618
authors.initials: MF
authors.lastname: Segura
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Zhang
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences &Shanghai Jiao Tong University School of Medicine, University of Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Guohong
authors.initials: G
authors.lastname: Hu
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics* / Q000502:physiology; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics* / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D035683:MicroRNAs; C538984:Mirn182 microRNA, human; C497806:SMAD7 protein, human; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta