Abstract
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.
Highlights
Malignant mesothelioma (MM) arises from the serosal mesothelial cells of somatic cavities and is an aggressive neoplasm [1,2,3,4]
We found that urokinase-type plasminogen activator receptor (uPAR) expression is associated with sensitivity to cisplatin in MM through the phosphatidyl inositide 3-kinase (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
The results showed that strong uPAR expression in rat MM was associated with significantly shorter survival during carcinogenesis (Figure 1E)
Summary
Malignant mesothelioma (MM) arises from the serosal mesothelial cells of somatic cavities and is an aggressive neoplasm [1,2,3,4]. While uPAR is normally expressed in various parts of the body, such as the colon, kidney, bronchus and bone marrow (www.proteinatlas.org), its expression increases during myeloid/monocytic differentiation [10], wound healing in keratinocytes [11] and the progression of www.impactjournals.com/oncotarget various neoplasms [12]. It was originally identified as a cell-surface binding site for urokinase-type plasminogen activator (uPA; Plau). The implications of these observed effects on the treatment and prognosis of MM are discussed
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