Collagen XVII/laminin-5 activates epithelial-to-mesenchymal transition and is associated with poor prognosis in lung cancer
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Chen-Chi Liu1, Jiun-Han Lin2,3, Tien-Wei Hsu2,3, Jyuan-Wei Hsu2,3, Jer-Wei Chang4, Kelly Su2,3, Han-Shui Hsu2,3 and Shih-Chieh Hung1,5,6,7,8
1Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
2Institute of Emergency and Critical Care Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan
3Division of Thoracic Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan
4Institute of Molecular and Genomic Medicine, National Health Research Institutes, Taipei, Taiwan
5Stem Cell Laboratory, Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan
6Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
7Integrative Stem Cell Center, Department of Orthopedics, China Medical University Hospital, Taichung, Taiwan
8Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
Han-Shui Hsu, email: [email protected]
Shih-Chieh Hung, email: [email protected]
Keywords: Collagen XVII, laminin-5, lung cancer, cancer stem-like cells, epithelial-to-mesenchymal transition (EMT)
Received: December 05, 2015 Accepted: July 27, 2016 Published: August 11, 2016
Epithelial-to-mesenchymal transition (EMT) is associated with tumor metastasis and tumorigenesis in lung cancer stem-like cells (CSCs). However, the exact mechanism underlying this is not clear. We used microarray analysis to identify candidate genes responsible for EMT in spheroid and monolayer cultures of lung cancer cells. We found increased expression of a variety of adhesion molecules in CSCs. One of these molecules, Collagen XVII (Col XVII), was demonstrated to be required for maintenance of EMT phenotypes and metastasis ability in lung CSCs. We showed that Col XVII stabilized laminin-5 to activate the FAK/AKT/GSK3β pathway, thereby suppressing Snail ubiquitination-degradation. The function of Col XVII was mainly dependent on shedding by ADAM9 and ADAM10. Patients who underwent surgical resection for lung cancer, and displayed overexpression of both Col XVII and laminin-5, had the worst prognosis of all expression types. Moreover, blockage of the Col XVII/laminin-5 pathway reduced the EMT phenotypes of lung CSCs in vitro and decreased the potential of lung metastasis in vivo. Our findings suggested that targeting Col XVII and laminin-5 could be novel therapeutic strategies for treating lung cancer patients, and warrant further investigation.
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