Multiple-level validation identifies PARK2 in the development of lung cancer and chronic obstructive pulmonary disease
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SeungBaek Lee1,*, Jun She2,3,*, Bo Deng3,4,*, JungJin Kim1,*, Mariza de Andrade3, Jie Na3, Zhifu Sun3, Jason A. Wampfler3, Julie M. Cunningham5, Yanhong Wu5, Andrew H. Limper6, Marie-Christine Aubry7, Chris Wendt8,9, Peter Biterman8, Ping Yang3, Zhenkun Lou1
1Division of Oncology Research, Mayo Clinic, Rochester, MN, USA
2Department of Pulmonary Medicine, Zhongshan Hospital, Fudan University, Shanghai, China
3Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
4Department of Thoracic Surgery, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing, China
5Genomics Shared Resource, Mayo Clinic, Rochester, MN, USA
6Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN, USA
7Division of Anatomic Pathology, Mayo Clinic, Rochester, MN, USA
8Department of Medicine, Pulmonary Division, University of Minnesota, Minneapolis, MN, USA
9Department of Medicine, Pulmonary Section, Minneapolis VA Medical Center, Minneapolis, MN, USA
*These authors have contributed equally to this work
Ping Yang, email: [email protected]
Zhenkun Lou, email: [email protected]
Keywords: lung cancer, chronic obstructive pulmonary disease, PARK2, inflammation
Received: January 27, 2016 Accepted: May 09, 2016 Published: June 13, 2016
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.
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