Multiple-level validation identifies<i>PARK2</i>in the development of lung cancer and chronic obstructive pulmonary disease

Abstract

// SeungBaek Lee 1, * , Jun She 2, 3, * , Bo Deng 3, 4, * , JungJin Kim 1, * , Mariza de Andrade 3 , Jie Na 3 , Zhifu Sun 3 , Jason A. Wampfler 3 , Julie M. Cunningham 5 , Yanhong Wu 5 , Andrew H. Limper 6 , Marie-Christine Aubry 7 , Chris Wendt 8, 9 , Peter Biterman 8 , Ping Yang 3 , Zhenkun Lou 1 1 Division of Oncology Research, Mayo Clinic, Rochester, MN, USA 2 Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China 3 Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA 4 Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China 5 Genomics Shared Resource, Mayo Clinic, Rochester, MN, USA 6 Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA 7 Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA 8 Department of Medicine, Pulmonary Division, University of Minnesota, Minneapolis, MN, USA 9 Department of Medicine, Pulmonary Section, Minneapolis VA Medical Center, Minneapolis, MN, USA * These authors have contributed equally to this work Correspondence to: Ping Yang, email: Yang.Ping@mayo.edu Zhenkun Lou, email: Lou.Zhenkun@mayo.edu Keywords: lung cancer, chronic obstructive pulmonary disease, PARK2 , inflammation Received: January 27, 2016&emsp;&emsp;&emsp;&emsp; Accepted: May 09, 2016&emsp;&emsp;&emsp;&emsp; Published: June 13, 2016 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-&kappa;B 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&lt;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.