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,...
| Main Authors: | , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2020-06-01
|
| Series: | Respiratory Research |
| Online Access: | http://link.springer.com/article/10.1186/s12931-020-01426-9 |
| _version_ | 1818239923833012224 |
|---|---|
| author | 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 |
| author_facet | 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 |
| author_sort | Ya-nan Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T13:05:16Z |
| format | Article |
| id | doaj.art-2454780b9efd47be824e11af44934a9a |
| institution | Directory Open Access Journal |
| issn | 1465-993X |
| language | English |
| last_indexed | 2024-12-12T13:05:16Z |
| publishDate | 2020-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Respiratory Research |
| spelling | doaj.art-2454780b9efd47be824e11af44934a9a2022-12-22T00:23:40ZengBMCRespiratory Research1465-993X2020-06-0121111410.1186/s12931-020-01426-9Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 productionYa-nan Liu0Yan Guan1Jian Shen2Yong-liang Jia3Jian-cang Zhou4Yun Sun5Jun-xia Jiang6Hui-juan Shen7Qiang Shu8Qiang-min Xie9Yicheng Xie10The Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthSir Run Run Shaw Hospital, Zhejiang University School of MedicineZhejiang Respiratory Drugs Research Laboratory of Food and Drug Administration of China, Zhejiang University School of MedicineZhejiang Respiratory Drugs Research Laboratory of Food and Drug Administration of China, Zhejiang University School of MedicineSir Run Run Shaw Hospital, Zhejiang University School of MedicineThe First People’s Hospital of YanchengZhejiang Respiratory Drugs Research Laboratory of Food and Drug Administration of China, Zhejiang University School of MedicineZhejiang Respiratory Drugs Research Laboratory of Food and Drug Administration of China, Zhejiang University School of MedicineThe Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthThe Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthThe Children’s Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child HealthAbstract 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.http://link.springer.com/article/10.1186/s12931-020-01426-9 |
| spellingShingle | 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 Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production Respiratory Research |
| title | Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production |
| title_full | Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production |
| title_fullStr | Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production |
| title_full_unstemmed | Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production |
| title_short | Shp2 positively regulates cigarette smoke-induced epithelial mesenchymal transition by mediating MMP-9 production |
| title_sort | shp2 positively regulates cigarette smoke induced epithelial mesenchymal transition by mediating mmp 9 production |
| url | http://link.springer.com/article/10.1186/s12931-020-01426-9 |
| work_keys_str_mv | AT yananliu shp2positivelyregulatescigarettesmokeinducedepithelialmesenchymaltransitionbymediatingmmp9production AT yanguan shp2positivelyregulatescigarettesmokeinducedepithelialmesenchymaltransitionbymediatingmmp9production AT jianshen shp2positivelyregulatescigarettesmokeinducedepithelialmesenchymaltransitionbymediatingmmp9production AT yongliangjia shp2positivelyregulatescigarettesmokeinducedepithelialmesenchymaltransitionbymediatingmmp9production AT jiancangzhou shp2positivelyregulatescigarettesmokeinducedepithelialmesenchymaltransitionbymediatingmmp9production AT yunsun shp2positivelyregulatescigarettesmokeinducedepithelialmesenchymaltransitionbymediatingmmp9production AT junxiajiang shp2positivelyregulatescigarettesmokeinducedepithelialmesenchymaltransitionbymediatingmmp9production AT huijuanshen shp2positivelyregulatescigarettesmokeinducedepithelialmesenchymaltransitionbymediatingmmp9production AT qiangshu shp2positivelyregulatescigarettesmokeinducedepithelialmesenchymaltransitionbymediatingmmp9production AT qiangminxie shp2positivelyregulatescigarettesmokeinducedepithelialmesenchymaltransitionbymediatingmmp9production AT yichengxie shp2positivelyregulatescigarettesmokeinducedepithelialmesenchymaltransitionbymediatingmmp9production |