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 () and Xiaotao Li ()
Additional contact information
Xiaohong Tan: Beijing Institute of LifeOmics
Lu Tong: University of Shanghai for Science and Technology
Lin Li: The Second Military Medical University
Jinjin Xu: East China Normal University
Shaofang Xie: East China Normal University
Lei Ji: East China Normal University
Junjiang Fu: Southwest Medical University
Qingwu Liu: East China Normal University
Shihui Shen: East China Normal University
Yun Liu: East China Normal University
Yanhui Xiao: East China Normal University
Feiran Gao: Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University
Robb E. Moses: Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza
Nabeel Bardeesy: Cancer Center, Massachusetts General Hospital
Yanxiao Wang: Beijing Institute of LifeOmics
Jishuai Zhang: Beijing Institute of LifeOmics
Longying Tang: Shanghai Changning Maternity and Infant Health Hospital.
Lei Li: University of Shanghai for Science and Technology
Kwok-kin Wong: New York University Langone Medical Center
Dianwen Song: Shanghai Jiao Tong University, School of Medicine
Xiao Yang: Beijing Institute of LifeOmics
Jian Liu: Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University
Xiaotao Li: East China Normal University

Nature Communications, 2021, vol. 12, issue 1, 1-11

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24898-9

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