@article {227, title = {Cul4A overexpression associated with Gli1 expression in malignant pleural mesothelioma.}, journal = {J Cell Mol Med}, volume = {19}, year = {2015}, month = {2015 Oct}, pages = {2385-96}, 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.

}, keywords = {Case-Control Studies, Cell Line, Tumor, Chi-Square Distribution, Cullin Proteins, Gene Dosage, Gene Expression Regulation, Neoplastic, Humans, Immunohistochemistry, Lung Neoplasms, Mesothelioma, Pleural Neoplasms, Real-Time Polymerase Chain Reaction, RNA, Messenger, Transcription Factors}, issn = {1582-4934}, doi = {10.1111/jcmm.12620}, author = {Yang, Yi-Lin and Ni, Jian and Hsu, Ping-Chih and Jiang-Hua Mao and Hsieh, David and Xu, Angela and Chan, Geraldine and Au, Alfred and Xu, Zhidong and Jablons, David M and You, Liang} } @article {208, title = {Lung tumourigenesis in a conditional Cul4A transgenic mouse model.}, journal = {J Pathol}, volume = {233}, year = {2014}, month = {2014 Jun}, pages = {113-23}, abstract = {

Cullin4A (Cul4A) is a scaffold protein that assembles cullin-RING ubiquitin ligase (E3) complexes and regulates many cellular events, including cell survival, development, growth and cell cycle control. Our previous study suggested that Cul4A is oncogenic in vitro, but its oncogenic role in vivo has not been studied. Here, we used a Cul4A transgenic mouse model to study the potential oncogenic role of Cul4A in lung tumour development. After Cul4A over-expression was induced in the lungs for 32 weeks, atypical epithelial cells were observed. After 40 weeks, lung tumours were visible and were characterized as grade I or II adenocarcinomas. Immunohistochemistry (IHC) revealed decreased levels of Cul4A-associated proteins p21(CIP1) and tumour suppressor p19(ARF) in the lung tumours, suggesting that Cul4A regulated their expression in these tumours. Increased levels of p27(KIP1) and p16(INK4a) were also detected in these tumours. Moreover, the protein level of DNA replication licensing factor CDT1 was decreased. Genomic instability in the lung tumours was further analysed by the results from pericentrin protein expression and array comparative genomic hybridization analysis. Furthermore, knocking down Cul4A expression in lung cancer H2170 cells increased their sensitivity to the chemotherapy drug cisplatin in vitro, suggesting that Cul4A over-expression is associated with cisplatin resistance in the cancer cells. Our findings indicate that Cul4A is oncogenic in vivo, and this Cul4A mouse model is a tool in understanding the mechanisms of Cul4A in human cancers and for testing experimental therapies targeting Cul4A.

}, keywords = {Adenocarcinoma, Animals, Antineoplastic Agents, Cell Cycle Proteins, Cell Line, Tumor, Cell Survival, Cell Transformation, Neoplastic, Cisplatin, Cullin Proteins, Cyclin-Dependent Kinase Inhibitor p16, Cyclin-Dependent Kinase Inhibitor p19, Cyclin-Dependent Kinase Inhibitor p21, Cyclin-Dependent Kinase Inhibitor p27, Disease Models, Animal, DNA-Binding Proteins, Dose-Response Relationship, Drug, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, Genomic Instability, Humans, Lung, Lung Neoplasms, Mice, Mice, Transgenic, Neoplasm Grading, Proliferating Cell Nuclear Antigen, RNA Interference, Time Factors, Transfection, Up-Regulation}, issn = {1096-9896}, doi = {10.1002/path.4352}, author = {Yang, Yi-Lin and Hung, Ming-Szu and Wang, Yang and Ni, Jian and Jiang-Hua Mao and Hsieh, David and Au, Alfred and Kumar, Atul and Quigley, David and Fang, Li Tai and Yeh, Che-Chung and Xu, Zhidong and Jablons, David M and You, Liang} } @article {190, title = {The expression of Dishevelled-3 and glutamine metabolism in malignant pleural mesothelioma.}, journal = {J Clin Pathol}, volume = {65}, year = {2012}, month = {2012 Sep}, pages = {855-8}, keywords = {Adaptor Proteins, Signal Transducing, Cell Line, Tumor, Excitatory Amino Acid Transporter 1, Glutamine, Humans, Immunohistochemistry, Kaplan-Meier Estimate, Mesothelioma, Multivariate Analysis, Phosphoproteins, Pleural Neoplasms, Polymerase Chain Reaction, Prognosis, Proportional Hazards Models, Tissue Array Analysis}, issn = {1472-4146}, doi = {10.1136/jclinpath-2011-200628}, author = {Li, Tong and Hou, Sheng-Cai and Jiang-Hua Mao and Wang, Yu-Cheng and Lu, Xiao-Dan and Tan, Jia-Li and You, Bin and Liu, Yu-Ping and Ni, Jian and Au, Alfred and Jablons, David M and Xu, Zhidong and You, Liang} }