Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation

Xiaohong Tan; Lu Tong; Lin Li; Jinjin Xu; Shaofang Xie; Lei Ji; Junjiang Fu; Qingwu Liu; Shihui Shen; Yun Liu; Yanhui Xiao; Feiran Gao; Robb E Moses; Nabeel Bardeesy; Yanxiao Wang; Jishuai Zhang; Longying Tang; Lei Li; Kwok-Kin Wong; Dianwen Song; Xiao Yang; Jian Liu; Xiaotao Li

doi:10.1038/s41467-021-24898-9

Loss of Smad4 promotes aggressive lung cancer metastasis by de-repression of PAK3 via miRNA regulation

Nat Commun. 2021 Aug 11;12(1):4853. doi: 10.1038/s41467-021-24898-9.

Authors

Xiaohong Tan^#¹, Lu Tong^#^{2

3}, Lin Li^#⁴, Jinjin Xu^#³, Shaofang Xie^#³, Lei Ji^#³, Junjiang Fu^#⁵, Qingwu Liu³, Shihui Shen³, Yun Liu³, Yanhui Xiao³, Feiran Gao^{6

7}, Robb E Moses⁸, Nabeel Bardeesy⁹, Yanxiao Wang¹, Jishuai Zhang¹, Longying Tang¹⁰, Lei Li², Kwok-Kin Wong¹¹, Dianwen Song¹², Xiao Yang¹³, Jian Liu^{14

15}, Xiaotao Li^{16

17

18}

Affiliations

¹ State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of LifeOmics, Beijing, China.
² Institute of Biomedical Engineering, School of Medical Instrument and Food Engineering, University of Shanghai for Science and Technology, Shanghai, China.
³ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China.
⁴ Department of Orthopedic Oncology, Changzheng Hospital, The Second Military Medical University, Shanghai, China.
⁵ Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China.
⁶ Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining, China.
⁷ Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
⁸ Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.
⁹ Cancer Center, Massachusetts General Hospital, Boston, MA, USA.
¹⁰ Shanghai Changning Maternity and Infant Health Hospital., Shanghai, China.
¹¹ Division of Hematology & Medical Oncology, Laura and Isaac Perlmutter Cancer Center, New York University Langone Medical Center, New York, NY, USA.
¹² Department of Orthopedics, Shanghai General Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China. dianwen_song@163.com.
¹³ 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.
¹⁴ Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University, Haining, China. JianL@intl.zju.edu.cn.
¹⁵ Department of Respiratory and Critical Care Medicine, the Second Affiliated Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China. JianL@intl.zju.edu.cn.
¹⁶ Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences, School of Life Sciences, East China Normal University, Shanghai, China. xiaotaol@bcm.edu.
¹⁷ Key Laboratory of Epigenetics and Oncology, The Research Center for Preclinical Medicine, Southwest Medical University, Luzhou, Sichuan, China. xiaotaol@bcm.edu.
¹⁸ Department of Molecular and Cellular Biology, Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA. xiaotaol@bcm.edu.

^# Contributed equally.

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 Kras^G12D, p53^fl/fl LOF and Smad4^fl/fl LOF mutations (SPK), showing a much higher incidence of tumor metastases than the Kras^G12D, p53^fl/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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

3' Untranslated Regions
Animals
Cell Movement
Gene Expression Regulation, Neoplastic
Humans
JNK Mitogen-Activated Protein Kinases / metabolism
Loss of Function Mutation
Lung Neoplasms / genetics
Lung Neoplasms / metabolism
Lung Neoplasms / pathology*
Mice
MicroRNAs / genetics*
MicroRNAs / metabolism
Neoplasm Metastasis
Proto-Oncogene Proteins c-jun / metabolism
Signal Transduction
Smad4 Protein / genetics
Smad4 Protein / metabolism*
Transcriptional Activation
p21-Activated Kinases / genetics
p21-Activated Kinases / metabolism*

Substances

3' Untranslated Regions
MIRN495 microRNA, human
MIRN543 microRNA, human
MicroRNAs
Proto-Oncogene Proteins c-jun
SMAD4 protein, human
Smad4 Protein
PAK3 protein, human
p21-Activated Kinases
JNK Mitogen-Activated Protein Kinases