title: Epigenetic down-regulation of integrin α7 increases migratory potential and confers poor prognosis in malignant pleural mesothelioma.
abstract: Malignant pleural mesothelioma (MPM) is a devastating malignancy characterized by invasive growth and rapid recurrence. The identification and inhibition of molecular components leading to this migratory and invasive phenotype are thus essential. Accordingly, a genome-wide expression array analysis was performed on MPM cell lines and a set of 139 genes was identified as differentially expressed in cells with high versus low migratory activity. Reduced expression of the novel tumour suppressor integrin α7 (ITGA7) was found in highly motile cells. A significant negative correlation was observed between ITGA7 transcript levels and average displacement of cells. Forced overexpression of ITGA7 in MPM cells with low endogenous ITGA7 expression inhibited cell motility, providing direct evidence for the regulatory role of ITGA7 in MPM cell migration. MPM cells showed decreased ITGA7 expressions at both transcription and protein levels when compared to non-malignant mesothelial cells. The majority of MPM cell cultures displayed hypermethylation of the ITGA7 promoter when compared to mesothelial cultures. A statistically significant negative correlation between ITGA7 methylation and ITGA7 expression was also observed in MPM cells. While normal human pleura samples unambiguously expressed ITGA7, a varying level of expression was found in a panel of 200 human MPM samples. In multivariate analysis, ITGA7 expression was found to be an independent prognostic factor. Although there was no correlation between histological subtypes and ITGA7 expression, importantly, patients with high tumour cell ITGA7 expression had an increased median overall survival compared to the low- or no-expression groups (463 versus 278 days). In conclusion, our data suggest that ITGA7 is an epigenetically regulated tumour suppressor gene and a prognostic factor in human MPM.
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.|Department of Biological Physics, Eötvös University, Budapest, Hungary.
authors.forename: Viktoria
authors.initials: V
authors.lastname: Laszlo
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.
authors.forename: Mir Alireza
authors.initials: MA
authors.lastname: Hoda
authors.affiliation: Department of Biological Physics, Eötvös University, Budapest, Hungary.|2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Tamas
authors.initials: T
authors.lastname: Garay
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.
authors.forename: Bahil
authors.initials: B
authors.lastname: Ghanim
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Klikovits
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.
authors.forename: Yawen W
authors.initials: YW
authors.lastname: Dong
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.|National Koranyi Institute of Pulmonology, Budapest, Hungary.
authors.forename: Anita
authors.initials: A
authors.lastname: Rozsas
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Istvan
authors.initials: I
authors.lastname: Kenessey
authors.affiliation: 2nd Department of Pathology, Semmelweis University, Budapest, Hungary.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Szirtes
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Grusch
authors.affiliation: University of Zagreb, School of Medicine, Department for Respiratory Diseases Jordanovac, University Hospital Center Zagreb, Croatia.
authors.forename: Marko
authors.initials: M
authors.lastname: Jakopovic
authors.affiliation: University of Zagreb, School of Medicine, Department for Respiratory Diseases Jordanovac, University Hospital Center Zagreb, Croatia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Samarzija
authors.affiliation: University of Zagreb, School of Medicine, Institute of Pathology, Croatia.|Institute of Pathology, Medical University of Graz, Austria.
authors.forename: Luka
authors.initials: L
authors.lastname: Brcic
authors.affiliation: University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.
authors.forename: Izidor
authors.initials: I
authors.lastname: Kern
authors.affiliation: University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.
authors.forename: Ales
authors.initials: A
authors.lastname: Rozman
authors.affiliation: Institute of Pathology, Medical University of Graz, Austria.
authors.forename: Helmut
authors.initials: H
authors.lastname: Popper
authors.affiliation: Division of Oncology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Zöchbauer-Müller
authors.affiliation: Division of Oncology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Gerwin
authors.initials: G
authors.lastname: Heller
authors.affiliation: Division of Oncology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Corinna
authors.initials: C
authors.lastname: Altenberger
authors.affiliation: Division of Oncology, Department of Medicine I, Comprehensive Cancer Center Vienna, Medical University of Vienna, Vienna, Austria.
authors.forename: Barbara
authors.initials: B
authors.lastname: Ziegler
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Klepetko
authors.affiliation: Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.|National Koranyi Institute of Pulmonology, Budapest, Hungary.|Department of Thoracic Surgery, National Institute of Oncology and Semmelweis University, Budapest, Hungary.|Department of Biomedical Imaging and Image-guided Therapy, Division of Molecular and Gender Imaging, Medical University of Vienna, Vienna, Austria.
authors.forename: Balazs
authors.initials: B
authors.lastname: Dome
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Comprehensive Cancer Center Vienna, Medical University of Vienna, Austria.|Institute of Cancer Research and Comprehensive Cancer Center, Department of Medicine I, Medical University of Vienna, Austria.|MTA-SE Molecular Oncology Research Group, Hungarian Academy of Sciences, Budapest, Hungary.
authors.forename: Balazs
authors.initials: B
authors.lastname: Hegedus
mesh_terms: D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D019175:DNA Methylation; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D039001:Integrin alpha Chains / Q000235:genetics / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D007797:Laminin / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008654:Mesothelioma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000086002:Mesothelioma, Malignant; D015999:Multivariate Analysis; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010997:Pleural Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D039001:Integrin alpha Chains; D007797:Laminin; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; C085725:integrin alpha7
keywords: cell migration; integrin; malignant pleural mesothelioma; prognosis; promoter methylation; tumour suppressor gene