Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma
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Shenqi Wang1, Li Jiang1, Yipeng Han2, Shan Hwu Chew1, Yuuki Ohara1, Shinya Akatsuka1, Liang Weng2, Koji Kawaguchi3, Takayuki Fukui3, Yoshitaka Sekido4,5, Kohei Yokoi3, Shinya Toyokuni1
1Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466–8550, Japan
2Department of Tumor Pathology, Nagoya University Graduate School of Medicine, Nagoya, 466–8550, Japan
3Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, 466–8550, Japan
4Department of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya, 466–8550, Japan
5Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, 464–8681, Japan
Shinya Toyokuni, email: firstname.lastname@example.org
Keywords: malignant mesothelioma, uPAR, cisplatin, AKT signaling pathway
Received: May 12, 2016 Accepted: August 25, 2016 Published: September 02, 2016
Malignant mesothelioma (MM) is a rare neoplasm associated with asbestos exposure. The prognosis of MM is poor because it is aggressive and highly resistant to chemotherapy. Using a rat model of asbestos-induced MM, we found elevated urokinase-type plasminogen activator receptor (uPAR; Plaur) expression in rat tissues, which was associated with poor prognosis. The proliferation, migration and invasion of MM cells were suppressed by uPAR knockdown and increased by overexpression experiments, irrespective of urokinase-type plasminogen activator (uPA; Plau) levels. More importantly, we found that uPAR expression is associated with sensitivity to cisplatin in MM through the PI3K/AKT pathway, which was demonstrated with specific inhibitors, LY294002 and Akti-1/2. uPAR knockdown significantly increased sensitivity to cisplatin whereas its overexpression significantly decreased cisplatin sensitivity. Furthermore, sera and tissues from MM patients showed significantly high uPAR levels, which suggested the pathogenic role of uPAR in the tumor biology of human MM. In conclusion, our findings indicate that uPAR levels are associated with malignant characteristics and cisplatin sensitivity of MM. In addition to the potential use of uPAR as a prognostic marker, the combination of uPAR abrogation and cisplatin may reveal a promising therapeutic approach for MM.
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