Periostin promotes epithelial-mesenchymal transition via the MAPK/miR-381 axis in lung cancer
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Wei-Wei Hu1,*, Po-Chun Chen2,3,4,*, Jun-Ming Chen2, Yue-Ming Wu1, Po-Yi Liu5,6, Chih-Hao Lu2, Yu-Feng Lin7, Chih-Hsin Tang4,5,8 and Chia-Chia Chao9
1Department of Thoracic Surgery, Dongyang People's Hospital, Dongyang, China
2Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan
3Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
4Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan
5Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan
6Department of Thoracic Surgery, Changhua Christian Hospital, Changhua, Taiwan
7Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan
8Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan
9Department of Respiratory Therapy, Fu-Jen Catholic University, New Taipei, Taiwan
*These authors have contributed equally to this work
Chia-Chia Chao, email: [email protected]
Chih-Hsin Tang, email: [email protected]
Keywords: periostin, lung cancer, epithelial-mesenchymal transition, miR-381, MAPK
Received: April 14, 2017 Accepted: May 29, 2017 Published: July 15, 2017
Periostin (POSTN, PN, or osteoblast-specific factor OSF-2) is a multifunctional cytokine that signals between the cell and the extracellular matrix. Periostin plays an important role in tumor development and is involved in carcinoma cell epithelial-mesenchymal transition (EMT), whereby mature epithelial cells undergo phenotypic morphological changes and become invasive, motile cells. Here, we discuss the molecular mechanisms involved in periostin-induced promotion of EMT in lung cancer cells. Online TCGA datasets demonstrate the prognostic relevance of periostin in lung cancer; a higher periostin level correlates with poor overall survival. Similarly, our IHC results show that high periostin expression is positively correlated with the EMT markers Snail and Twist, as well as stage of lung cancer. We found that recombinant periostin induces the EMT phenotype in lung cancer cells through the p38/ERK pathway, while pretreatment with chemical inhibitors prevented periostin-induced EMT induction. Moreover, we found that periostin regulates EMT by repressing microRNA-381 (miR-381) expression, which targets both Snail and Twist. Using the miR-381 mimic, we dramatically reversed periostin-induced Snail and Twist expression. Furthermore, periostin knockdown dramatically affected EMT markers and cell migration potential. The role of periostin in lung cancer progression is elucidated by the in vivo mouse model. Our findings indicate that changes in periostin expression in lung cancer may serve as a therapeutic target for the treatment of lung cancer metastasis.
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