Abstract
Malignant pleural mesothelioma (mesothelioma) is a highly aggressive cancer without an effective treatment. Cul4A, a scaffold protein that recruits substrates for degradation, is amplified in several human cancers, including mesothelioma. We have recently shown that Cul4A plays an oncogenic role in vitro and in a mouse model. In this study, we analysed clinical mesothelioma tumours and found moderate to strong expression of Cul4A in 70.9% (51/72) of these tumours, as shown by immunohistochemistry. In 72.2% mesothelioma tumours with increased Cul4A copy number identified by fluorescence in situ hybridization analysis, Cul4A protein expression was moderate to strong. Similarly, Cul4A was overexpressed and Cul4A copy number was increased in human mesothelioma cell lines. Because Gli1 is highly expressed in human mesothelioma cells, we compared Cul4A and Gli1 expression in mesothelioma tumours and found their expression associated (P < 0.05, chi-square). In mesothelioma cell lines, inhibiting Cul4A by siRNA decreased Gli1 expression, suggesting that Gli1 expression is, at least in part, regulated by Cul4A in mesothelioma cells. Our results suggest a linkage between Cul4A and Gli1 expression in human mesothelioma.
Highlights
Malignant pleural mesothelioma is a highly aggressive cancer that arises primarily from the pleural lining of the lung
Human mesothelial LP-9 cells and lymphocytes showed two copies of Cullin 4A (Cul4A). Since these results indicated that Cul4A copy number is increased in most of the analysed mesothelioma cell lines, we analysed Cul4A protein expression in these cell lines using IHC
Our study shows that in mesothelioma tumours and human mesothelioma cell lines, Cul4A is overexpressed and Cul4A copy number is increased
Summary
Malignant pleural mesothelioma (mesothelioma) is a highly aggressive cancer that arises primarily from the pleural lining of the lung. The disease usually presents at an advanced stage and has a poor prognosis. The mechanisms of mesothelioma pathogenesis have not been fully elucidated and there is no effective treatment. New therapeutic development is needed based on a greater understanding of mesothelioma’s underlying molecular mechanisms. Cullin 4A (Cul4A), an evolutionally conserved cullin protein, provides a scaffold for ubiquitin ligases (E3) and functions in mediating proteolysis to regulate many cellular processes, including cell cycle, development, apoptosis and genome instability [1].
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