title: Analysis of microRNA expression signatures in malignant pleural mesothelioma, pleural inflammation, and atypical mesothelial hyperplasia reveals common predictive tumorigenesis-related targets.
abstract: Pleural chronic inflammation (PP) and mesothelial hyperplasia (HP) may be critical to the development of malignant pleural mesothelioma (MPM). Nonetheless, studies searching for mechanistic links involving microRNA (miRNA) regulation among these interrelated processes have not been reported. Using PCR-Array, we identified the miRNAs expressed in pleural tissues diagnosed with MPM (n=5), PP (n=4) and HP (n=5), as well as in non-cancerous/non-inflammatory tissue as the normal control (n=5). We performed bioinformatics and network analysis of differentially expressed miRNAs to identify tumorigenesis-related miRNAs and their biological networks. The targets of four down-regulated miRNAs in MPM (mir-181a-5p, miR-101-3p, miR-145-5p and miR-212-3p), one in PP (mir-101-3p) and one in HP (mir-494) were significantly enriched in "pathways in cancer". Interactome networks revealed that >50% of down-regulated miRNAs in MPM targeted the signaling-activation molecule MAPK1, the transcription factor ETS1 and the mesenchymal transition-associated molecule FZDA, which have been associated with oncogenic function. Comparative analysis revealed that FZD4 was an overlapping gene target of down-regulated miRNAs that were associated with "pathways in cancer" in MPM, PP and HP. Moreover, MAPK1, ETS1 and Cox-2, a pro-inflammatory enzyme associated with over-expression in cancers, were among the 25 overlapping target genes in MPM and PP. This network analysis revealed a potential combinatory effect of deregulated miRNAs in MPM pathogenesis and indicated potential molecular links between pleural inflammation and hyperplasia with tumorigenesis mechanisms in pleura.
authors.affiliation: Faculty of Medicine, Universidad Autónoma de México, Mexico City, Mexico.
authors.forename: Eric Gustavo
authors.initials: EG
authors.lastname: Ramírez-Salazar
authors.affiliation: Research Unit, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico.
authors.forename: Luis Carlos
authors.initials: LC
authors.lastname: Salinas-Silva
authors.affiliation: Department of Pathology, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico.
authors.forename: Maria Eugenia
authors.initials: ME
authors.lastname: Vázquez-Manríquez
authors.affiliation: Research Unit, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico.
authors.forename: Luis Vicente
authors.initials: LV
authors.lastname: Gayosso-Gómez
authors.affiliation: Research Unit, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Negrete-Garcia
authors.affiliation: Research Unit, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico.
authors.forename: Sandra Lizbeth
authors.initials: SL
authors.lastname: Ramírez-Rodriguez
authors.affiliation: Faculty of Medicine, Universidad Autónoma de México, Mexico City, Mexico.
authors.forename: Raúl
authors.initials: R
authors.lastname: Chávez
authors.affiliation: Faculty of Medicine, Universidad Autónoma de México, Mexico City, Mexico.
authors.forename: Edgar
authors.initials: E
authors.lastname: Zenteno
authors.affiliation: Department of Thoracic Surgery, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico.
authors.forename: Patricio
authors.initials: P
authors.lastname: Santillán
authors.affiliation: Oncology Service, Centro Médico Siglo XXI, Mexico City, Mexico.
authors.forename: Javier
authors.initials: J
authors.lastname: Kelly-García
authors.affiliation: Research Unit, Instituto Nacional de Enfermedades Respiratorias "Ismael Cosio Villegas", Mexico City, Mexico. Electronic address: boq@iner.gob.mx.
authors.forename: Blanca
authors.initials: B
authors.lastname: Ortiz-Quintero
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D063646:Carcinogenesis / Q000235:genetics*; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000235:genetics / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000473:pathology; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008654:Mesothelioma / Q000235:genetics* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D035683:MicroRNAs / Q000032:analysis*; D008875:Middle Aged; D010997:Pleural Neoplasms / Q000235:genetics* / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics*; D059467:Transcriptome; D055815:Young Adult
chemical_list: D035683:MicroRNAs
keywords: Malignant pleural mesothelioma; Mesothelial hyperplasia; MicroRNAs; Pleural inflammation; Tumorigenesis