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Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation.
Tan, Xiaohong; Tong, Lu; Li, Lin; Xu, Jinjin; Xie, Shaofang; Ji, Lei; Fu, Junjiang; Liu, Qingwu; Shen, Shihui; Liu, Yun; Xiao, Yanhui; Gao, Feiran; Moses, Robb E; Bardeesy, Nabeel; Wang, Yanxiao; Zhang, Jishuai; Tang, Longying; Li, Lei; Wong, Kwok-Kin; Song, Dianwen; Yang, Xiao; Liu, Jian; Li, Xiaotao.
Afiliação
  • Tan X; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of LifeOmics, Beijing, China.
  • Tong L; Institute of Biomedical Engineering, School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China.
  • Li L; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
  • Xu J; Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai, China.
  • Xie S; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
  • Ji L; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
  • Fu J; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
  • Liu Q; Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China.
  • Shen S; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
  • Liu Y; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
  • Xiao Y; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
  • Gao F; Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
  • Moses RE; Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining, China.
  • Bardeesy N; Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
  • Wang Y; Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.
  • Zhang J; Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
  • Tang L; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of LifeOmics, Beijing, China.
  • Li L; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of LifeOmics, Beijing, China.
  • Wong KK; Shanghai Changning Maternity and Infant Health Hospital., Shanghai, China.
  • Song D; Institute of Biomedical Engineering, School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China.
  • Yang X; Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
  • Liu J; Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China. dianwen_song@163.com.
  • Li X; State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of LifeOmics, Beijing, China. yangx@bmi.ac.cn.
Nat Commun ; 12(1): 4853, 2021 08 11.
Article em En | MEDLINE | ID: mdl-34381046
ABSTRACT
SMAD4 is mutated in human lung cancer, but the underlying mechanism by which Smad4 loss-of-function (LOF) accelerates lung cancer metastasis is yet to be elucidated. Here, we generate a highly aggressive lung cancer mouse model bearing conditional KrasG12D, p53fl/fl LOF and Smad4fl/fl LOF mutations (SPK), showing a much higher incidence of tumor metastases than the KrasG12D, p53fl/fl (PK) mice. Molecularly, PAK3 is identified as a downstream effector of Smad4, mediating metastatic signal transduction via the PAK3-JNK-Jun pathway. Upregulation of PAK3 by Smad4 LOF in SPK mice is achieved by attenuating Smad4-dependent transcription of miR-495 and miR-543. These microRNAs (miRNAs) directly bind to the PAK3 3'UTR for blockade of PAK3 production, ultimately regulating lung cancer metastasis. An inverse correlation between Smad4 and PAK3 pathway components is observed in human lung cancer. Our study highlights the Smad4-PAK3 regulation as a point of potential therapy in metastatic lung cancer.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: MicroRNAs / Proteína Smad4 / Quinases Ativadas por p21 / Neoplasias Pulmonares Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: MicroRNAs / Proteína Smad4 / Quinases Ativadas por p21 / Neoplasias Pulmonares Idioma: En Ano de publicação: 2021 Tipo de documento: Article