Endothelin-1 promotes epithelial-mesenchymal transition in human chondrosarcoma cells by repressing miR-300.
Chondrosarcoma is a malignant tumor of mesenchymal origin predominantly composed of cartilage-producing cells. This type of bone cancer is extremely resistant to radiotherapy and chemotherapy. Surgical resection is the primary treatment, but is often difficult and not always practical for metastatic disease, so more effective treatments are needed. In particular, it would be helpful to identify molecular markers as targets for therapeutic intervention. Endothelin-1 (ET-1), a potent vasoconstrictor, has been shown to enhance chondrosarcoma angiogenesis and metastasis. We report that ET-1 promotes epithelial-mesenchymal transition (EMT) in human chondrosarcoma cells. EMT is a key pathological event in cancer progression, during which epithelial cells lose their junctions and apical-basal polarity and adopt an invasive phenotype. Our study verifies that ET-1 induces the EMT phenotype in chondrosarcoma cells via the AMP-activated protein kinase (AMPK) pathway. In addition, we show that ET-1 increases EMT by repressing miR-300, which plays an important role in EMT-enhanced tumor metastasis. We also show that miR-300 directly targets Twist, which in turn results in a negative regulation of EMT. We found a highly positive correlation between ET-1 and Twist expression levels as well as tumor stage in chondrosarcoma patient specimens. Therefore, ET-1 may represent a potential novel molecular therapeutic target in chondrosarcoma metastasis.
Physical Education Office, Tunghai University, Taichung, Taiwan.|Sports Recreation and Health Management Continuing Studies, Tunghai University, Taichung, Taiwan.
Min-Huan
MH
Wu
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.
Pei-Han
PH
Huang
Department of Life Science, Tunghai University, Taichung, Taiwan.
Mingli
M
Hsieh
Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.|School of Medicine, China Medical University, Taichung, Taiwan.
Chun-Hao
CH
Tsai
Department of Orthopedic Surgery, China Medical University Hospital, Taichung, Taiwan.|School of Chinese Medicine, China Medical University, Taichung, Taiwan.
Hsien-Te
HT
Chen
Graduate Institute of Basic Medical Science, China Medical University, Taichung, Taiwan.|School of Medicine, China Medical University, Taichung, Taiwan.|Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan.
Chih-Hsin
CH
Tang
D020413:3' Untranslated Regions; D055372:AMP-Activated Protein Kinases / Q000502:physiology; D001859:Bone Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002813:Chondrosarcoma / Q000473:pathology*; D019332:Endothelin-1 / Q000494:pharmacology*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D035683:MicroRNAs / Q000037:antagonists & inhibitors*; D009687:Nuclear Proteins / Q000235:genetics / Q000502:physiology; D017466:Receptors, Endothelin / Q000502:physiology; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000502:physiology
D020413:3' Untranslated Regions; D019332:Endothelin-1; C000596512:MIRN300 microRNA, human; D035683:MicroRNAs; D009687:Nuclear Proteins; D017466:Receptors, Endothelin; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D055372:AMP-Activated Protein Kinases
AMPK; Twist; epithelial to mesenchymal transition; miR-300; endothelin-1