title: Multiple-level validation identifies PARK2 in the development of lung cancer and chronic obstructive pulmonary disease.
abstract: An important precursor to lung cancer development is chronic obstructive pulmonary disease (COPD), independent of exposure to tobacco smoke. Both diseases are associated with increased host susceptibility, inflammation, and genomic instability. However, validation of the candidate genes and functional confirmation to test shared genetic contribution and cellular mechanisms to the development of lung cancer in patients with COPD remains underexplored. Here, we show that loss of PARK2 (encoding Parkin) increases the expression of proinflammation factors as well as nuclear NF-κB localization, suggesting a role of PARK2 loss in inflammation. Additional exploration showed that PARK2 deficiency promotes genomic instability and cell transformation. This role of PARK2 in inflammation and chromosome instability provides a potential link among Parkin, COPD and lung cancer. A further comprehensive validation of 114 informative single nucleotide polymorphism (SNP) variants of PARK2, in 2,484 cases and controls with well-defined lung cancer and COPD phenotypes, found rs577876, rs6455728 and rs9346917 (p<0.01) to be significantly associated with lung cancer development in people with COPD. Our findings support the evidence that PARK2 might have a tumor suppressor role in the development of COPD and lung cancer.
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: SeungBaek
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China.|Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: She
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.|Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Deng
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: JungJin
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mariza
authors.initials: M
authors.lastname: de Andrade
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Na
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Zhifu
authors.initials: Z
authors.lastname: Sun
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Wampfler
authors.affiliation: Genomics Shared Resource, Mayo Clinic, Rochester, MN, USA.
authors.forename: Julie M
authors.initials: JM
authors.lastname: Cunningham
authors.affiliation: Genomics Shared Resource, Mayo Clinic, Rochester, MN, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Limper
authors.affiliation: Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Aubry
authors.affiliation: Department of Medicine, Pulmonary Division, University of Minnesota, Minneapolis, MN, USA.|Department of Medicine, Pulmonary Section, Minneapolis VA Medical Center, Minneapolis, MN, USA.
authors.forename: Chris
authors.initials: C
authors.lastname: Wendt
authors.affiliation: Department of Medicine, Pulmonary Division, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Biterman
authors.affiliation: Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Yang
authors.affiliation: Division of Oncology Research, Mayo Clinic, Rochester, MN, USA.
authors.forename: Zhenkun
authors.initials: Z
authors.lastname: Lou
mesh_terms: D000072283:A549 Cells; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000378:metabolism; D015810:Linkage Disequilibrium; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics* / Q000378:metabolism; D015203:Reproducibility of Results; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D016207:Cytokines; D016328:NF-kappa B; D044767:Ubiquitin-Protein Ligases; C111567:parkin protein
keywords: PARK2; chronic obstructive pulmonary disease; inflammation; lung cancer