title: Frequent coamplification and cooperation between C-MYC and PVT1 oncogenes promote malignant pleural mesothelioma.
abstract: BACKGROUND
  Malignant pleural mesothelioma (MPM) is a deadly disease with poor prognosis and few treatment options. We characterized and elucidated the roles of C-MYC and PVT1 involved in the pathogenesis of MPM.
  
  
  METHODS
  We used small interfering RNA (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 spanning the PVT1 region in MPM cell lines. Copy number analysis was measured by quantitative polymerase chain reaction and fluorescence in situ hybridization.
  
  
  RESULTS
  Copy number analysis revealed copy number gains (CNGs) in chromosomal region 8q24 in six of 12 MPM cell lines. MicroRNA analysis showed high miR-1204 expression in MSTO-211H cell lines with four copies or more 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 proapoptotic and antiapoptotic gene expression, whereas PVT1 and, to a lesser extent, miR-1204 up-regulate proapoptotic genes and down-regulate antiapoptotic genes. Fluorescence in situ hybridization analysis of MPM tumor specimens showed a high frequency of both CNGs (11 of 75) and trisomy (three copies; 11 of 75) for the C-MYC locus.
  
  
  CONCLUSIONS
  Our results suggest that C-MYC and PVT1 CNG promotes a malignant phenotype of MPM, with C-MYC CNG stimulating cell proliferation and PVT1 both stimulating proliferation and inhibiting apoptosis.
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Erick
authors.initials: E
authors.lastname: Riquelme
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Milind B
authors.initials: MB
authors.lastname: Suraokar
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Jaime
authors.initials: J
authors.lastname: Rodriguez
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Barbara
authors.initials: B
authors.lastname: Mino
authors.affiliation: Department of Biostatistics, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Heather Y
authors.initials: HY
authors.lastname: Lin
authors.affiliation: Departments of Thoracic and Cardiovascular Surgery, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: David C
authors.initials: DC
authors.lastname: Rice
authors.affiliation: Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
authors.forename: Anne
authors.initials: A
authors.lastname: Tsao
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; Departments of Thoracic/Head and Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas. Electronic address: iiwistuba@mdanderson.org.
authors.forename: Ignacio I
authors.initials: II
authors.lastname: Wistuba
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis; D063646:Carcinogenesis / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002898:Chromosomes, Human, Pair 8; D002945:Cisplatin / Q000494:pharmacology; D005784:Gene Amplification; D018628:Gene Dosage; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D016259:Genes, myc / Q000235:genetics*; D056426:Genetic Loci; D006801:Humans; D008654:Mesothelioma / Q000737:chemistry / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D010997:Pleural Neoplasms / Q000737:chemistry / Q000235:genetics*; D062085:RNA, Long Noncoding / Q000235:genetics*; D012333:RNA, Messenger / Q000032:analysis
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; C521123:PVT1 long-non-coding RNA, human; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D002945:Cisplatin