Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production.

Abstract

Cigarette smoke (CS) is a major risk factor for the development of lung cancer and chronic obstructive pulmonary disease (COPD). Epithelial-mesenchymal transition (EMT) commonly coexists in lung cancer and COPD. CS triggers many factors including matrix metalloproteinases (MMPs) production, contributing to EMT progression in the lungs. Here, how Shp2 signaling regulates the CS-induced MMP-9 production and EMT progression were investigated in mouse lungs and in pulmonary epithelial cell cultures (NCI-H292) found CS induced MMP-9 production, EMT progression (increased vimentin and α-SMA; decreased E-cadherin) and collagen deposition in lung tissues; cigarette smoke extract (CSE) induced MMP-9 production and EMT-related phenotypes in NCI-H292 cells, which were partially prevented by Shp2 KO/KD or Shp2 inhibition. The CSE exposure induced EMT phenotypes were suppressed by MMP-9 inhibition. Recombinant MMP-9 induced EMT, which was prevented by MMP-9 inhibition or Shp2 KD/inhibition. Mechanistically, CS and CSE exposure resulted in ERK1/2, JNK and Smad2/3 phosphorylation, which were suppressed by Shp2 KO/KD/inhibition. Consequentially, the CSE exposure-induced MMP-9 production and EMT progression were suppressed by ERK1/2, JNK and Smad2/3 inhibitors. Thus, CS induced MMP-9 production and EMT resulted from activation of Shp2/ERK1/2/JNK/Smad2/3 signaling pathways. Our study contributes to the underlying mechanisms of pulmonary epithelial structural changes in response to CS, which may provide novel therapeutic solutions for treating associated diseases, such as COPD and lung cancer.

• Authors: Ya-Nan Liu, Yan Guan, Jian Shen, Yong-Liang Jia, Jian-Cang Zhou, Yun Sun, Jun-Xia Jiang, Hui-Juan Shen, Qiang Shu, Qiang-Min Xie, Yicheng Xie
• Journal: Respiratory research (Respir Res) Vol. 21 Issue 1 Pg. 161 (Jun 26 2020) ISSN: 1465-993X [Electronic] England
• PMID: 32586329 (Publication Type: Journal Article, Retracted Publication)

Chemical References

• Protein Tyrosine Phosphatase, Non-Receptor Type 11
• Ptpn11 protein, mouse
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• Cell Line, Tumor
• Cigarette Smoking (adverse effects, metabolism)
• Epithelial-Mesenchymal Transition (drug effects, physiology)
• Humans
• Inhalation Exposure (adverse effects)
• Matrix Metalloproteinase 9 (biosynthesis)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Protein Tyrosine Phosphatase, Non-Receptor Type 11 (biosynthesis)
• Pulmonary Disease, Chronic Obstructive (metabolism, pathology)