Urokinase-type plasminogen activator receptor promotes proliferation and invasion with reduced cisplatin sensitivity in malignant mesothelioma.
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.
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Shenqi
S
Wang
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Li
L
Jiang
Department of Tumor Pathology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Yipeng
Y
Han
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Shan Hwu
SH
Chew
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Yuuki
Y
Ohara
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Shinya
S
Akatsuka
Department of Tumor Pathology, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Liang
L
Weng
Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Koji
K
Kawaguchi
Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Takayuki
T
Fukui
Department of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.|Division of Molecular Oncology, Aichi Cancer Center Research Institute, Nagoya, 464-8681, Japan.
Yoshitaka
Y
Sekido
Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Kohei
K
Yokoi
Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, 466-8550, Japan.
Shinya
S
Toyokuni
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D001194:Asbestos; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D008654:Mesothelioma / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism; D000086002:Mesothelioma, Malignant; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D051381:Rats; D055293:Receptors, Urokinase Plasminogen Activator / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous
D000970:Antineoplastic Agents; D055293:Receptors, Urokinase Plasminogen Activator; D001194:Asbestos; D002945:Cisplatin
AKT signaling pathway; cisplatin; malignant mesothelioma; uPAR