Abstract
Abstract It is a well-known fact that malignant mesothelioma is primarily caused by the exposure to asbestos. Due to the widespread use of asbestos, cases of malignant mesothelioma are increasing at a dramatic rate. Histopathological examinations have revealed different subtypes of malignant mesothelioma. Based on cellular morphology, it is classified into epithelial (EM), sarcomatous (SM) and biphasic (BM) (containing a mixture of epithelial and sarcomatous cells) subtypes. Although sarcomatous mesothelioma is not as common as epithelial mesothelioma, it is recognized as the most aggressive type of malignant mesothelioma and patients diagnosed with this type of mesothelioma usually have a remarkably short survival period. Driven by the interest to know what are the molecular mechanisms underlying the relatively more aggressive phenotype of sarcomatous mesothelioma, we have initiated our study. From the microarray results, we have singled out a candidate gene (connective tissue growth factor, CTGF) whose expression is significantly increased in SM samples compared to the EM and normal control. We found CTGF regulated mesothelioma cells, especial SM cells proliferation, migration, invasion via activating β-catenin-T-cell factor/Lef signaling pathway. Mesothelioma cells decreased proliferation, migration, invasion after knockdown CTGF. We injected mesothelioma cells or CTGF-knockdown mesothelioma cells into nude mice. The tumor size of CTGF-knockdown mesothelioma injection is significant smaller than non-treated mesothelioma, especially in SM. We also found a causal association between high CTGF expression and the poor prognosis of sarcomatous mesothelioma and that the underlying molecular mechanism is related to the promotion of EMT (epithelial-mesenchymal transition) by CTGF. Many EMT regulators including Slug, Snail and Twist have been activated when over-expressed CTGF in EM. Conversely, the MET also is found when knockdown CTGF in SM. Our study is expected to have a great impact by offering novel therapeutic targets which are urgently needed at present. Our preliminary data appears to be very promising and we are highly confident that through the manipulation of our candidate gene, we will be able to at least greatly reduce the malignancy of sarcomatous subtype of mesothelioma and extend patient's lifespan, if not fully cure it. Citation Format: Li Jiang. CTGF is overexpression in asbestos-induced malignant mesothelioma and promotes beta-catenin-T-cell factor/Lef signaling. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 300. doi:10.1158/1538-7445.AM2013-300
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