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

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.

• Authors: 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
• Journal: Nature communications (Nat Commun) Vol. 12 Issue 1 Pg. 4853 (08 11 2021) ISSN: 2041-1723 [Electronic] England
• PMID: 34381046 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021. The Author(s).

Chemical References

• 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

Topics

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