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Deprecated: Implicit conversion from float 265.2 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 J+Thorac+Oncol 2014 ; 9 (7): 998-1007 Nephropedia Template TP
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Frequent co-amplification and co-operation between C-MYC and PVT1 oncogenes promote malignant pleural mesothelioma #MMPMID24926545
Riquelme E; Suraokar MB; Rodriguez J; Mino B; Lin HY; Rice DC; Tsao A; Wistuba II
J Thorac Oncol 2014[Jul]; 9 (7): 998-1007 PMID24926545show ga
Introduction: Malignant pleural mesothelioma (MPM) is a deadly disease with poor prognosis and few treatment options. We characterized and elucidate the roles of C-MYC and PVT1 involved in the pathogenesis of MPM. Methods: We used siRNA-mediated knockdown in MPM cell lines to determine the effect of C-MYC and PVT1 abrogation on MPM cells undergoing apoptosis, proliferation, and cisplatin sensitivity. We also characterized the expression of microRNAs (miRNAs) spanning the PVT1 region in MPM cell lines. Copy number analysis was measured by quantitative PCR and fluorescence in situ hybridization. Results: Copy number analysis revealed copy number gains (CNGs) in chromosomal region 8q24 in six of twelve MPM cell lines. MicroRNA analysis showed high miR-1204 expression in MSTO-211H cell lines with ?4 copies of PVT1. Knockdown by siRNA showed increased PARP-C levels in MSTO-211H transfected with siPVT1 but not in cells transfected with siC-MYC. C-MYC and PVT1 knockdown reduced cell proliferation and increased sensitivity to cisplatin. Analysis of the expression of apoptosis-related genes in the MSTO-211H cell line suggested that C-MYC maintains a balance between pro-apoptotic and anti-apoptotic gene expression, whereas PVT1 and to a lesser extent miR-1204, upregulate pro-apoptotic genes and downregulate anti-apoptotic genes. FISH analysis of MPM tumor specimens showed a high frequency of both CNGs (11/75) and trisomy (three copies; 11/75) for the C-MYC locus. Conclusion: Our results suggest that C-MYC and PVT1 copy number gain promotes a malignant phenotype of MPM, with C-MYC CNG stimulating cell proliferation and PVT1 both stimulating proliferation and inhibiting apoptosis.