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

Seung Baek Lee; Jun She; Bo Deng; Jung Jin Kim; Mariza de Andrade; Jie Na; Zhifu Sun; Jason A. Wampfler; Julie M. Cunningham; Yanhong Wu; Andrew H. Limper; Marie Christine Aubry; Chris Wendt; Peter Biterman; Ping Yang; Zhenkun Lou

doi:10.18632/oncotarget.9954

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

Seung Baek Lee, Jun She, Bo Deng, Jung Jin Kim, Mariza de Andrade, Jie Na, Zhifu Sun, Jason A. Wampfler, Julie M. Cunningham, Yanhong Wu, Andrew H. Limper, Marie Christine Aubry, Chris Wendt, Peter Biterman, Ping Yang, Zhenkun Lou

Research output: Contribution to journal › Article › peer-review

42 Scopus citations

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.

Original language	English (US)
Pages (from-to)	44211-44223
Number of pages	13
Journal	Oncotarget
Volume	7
Issue number	28
DOIs	https://doi.org/10.18632/oncotarget.9954
State	Published - 2016

Bibliographical note

Funding Information:
The study was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant, R01-HL107612 (Yang and Wendt), and National Cancer Institute grants, R01-CA80127 (Yang), R01-CA84354 (Yang), R01-CA130996 (Lou), R01-CA108961 (Lou) and R01-CA148940 (Lou), and Mayo Clinic Foundation Funds (Yang and Lou), Mayo Clinic Cancer Center grant CA15083. We thank Dr. Thomas C. Smyrk (Mayo clinic) for IHC analysis. Jun She was supported by the National Natural Science Foundation for Young Scholars of China, No. 81200051 and Scientific Project for Fudan University, No. 20520133474. Bo Deng was supported by National Natural Science Foundation of China, No. 81101782 and Third Military Medical University MiaoPu project. Ola Larsson was supported by the Swedish Research Council and the Wallenbberg Academy Fellows Programme. Andrew Limper was supported by funds from the Annenberg Foundation. Biospeciens accessioning and processing, genotyping and RNA microarray analysis were supported partly by the Mayo Clinic Cancer Center grant CA15083.

Keywords

Chronic obstructive pulmonary disease
Inflammation
Lung cancer
PARK2

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.18632/oncotarget.9954

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Lee, S. B., She, J., Deng, B., Kim, J. J., de Andrade, M., Na, J., Sun, Z., Wampfler, J. A., Cunningham, J. M., Wu, Y., Limper, A. H., Aubry, M. C., Wendt, C., Biterman, P., Yang, P., & Lou, Z. (2016). Multiple-level validation identifies PARK2 in the development of lung cancer and chronic obstructive pulmonary disease. Oncotarget, 7(28), 44211-44223. https://doi.org/10.18632/oncotarget.9954

Lee, SB, She, J, Deng, B, Kim, JJ, de Andrade, M, Na, J, Sun, Z, Wampfler, JA, Cunningham, JM, Wu, Y, Limper, AH, Aubry, MC, Wendt, C, Biterman, P, Yang, P & Lou, Z 2016, 'Multiple-level validation identifies PARK2 in the development of lung cancer and chronic obstructive pulmonary disease', Oncotarget, vol. 7, no. 28, pp. 44211-44223. https://doi.org/10.18632/oncotarget.9954

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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.",

keywords = "Chronic obstructive pulmonary disease, Inflammation, Lung cancer, PARK2",

author = "Lee, {Seung Baek} and Jun She and Bo Deng and Kim, {Jung Jin} and {de Andrade}, Mariza and Jie Na and Zhifu Sun and Wampfler, {Jason A.} and Cunningham, {Julie M.} and Yanhong Wu and Limper, {Andrew H.} and Aubry, {Marie Christine} and Chris Wendt and Peter Biterman and Ping Yang and Zhenkun Lou",

note = "Funding Information: The study was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant, R01-HL107612 (Yang and Wendt), and National Cancer Institute grants, R01-CA80127 (Yang), R01-CA84354 (Yang), R01-CA130996 (Lou), R01-CA108961 (Lou) and R01-CA148940 (Lou), and Mayo Clinic Foundation Funds (Yang and Lou), Mayo Clinic Cancer Center grant CA15083. We thank Dr. Thomas C. Smyrk (Mayo clinic) for IHC analysis. Jun She was supported by the National Natural Science Foundation for Young Scholars of China, No. 81200051 and Scientific Project for Fudan University, No. 20520133474. Bo Deng was supported by National Natural Science Foundation of China, No. 81101782 and Third Military Medical University MiaoPu project. Ola Larsson was supported by the Swedish Research Council and the Wallenbberg Academy Fellows Programme. Andrew Limper was supported by funds from the Annenberg Foundation. Biospeciens accessioning and processing, genotyping and RNA microarray analysis were supported partly by the Mayo Clinic Cancer Center grant CA15083.",

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doi = "10.18632/oncotarget.9954",

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AU - She, Jun

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AU - Kim, Jung Jin

AU - de Andrade, Mariza

AU - Na, Jie

AU - Sun, Zhifu

AU - Wampfler, Jason A.

AU - Cunningham, Julie M.

AU - Wu, Yanhong

AU - Limper, Andrew H.

AU - Aubry, Marie Christine

AU - Wendt, Chris

AU - Biterman, Peter

AU - Yang, Ping

AU - Lou, Zhenkun

N1 - Funding Information: The study was supported by the National Heart, Lung, and Blood Institute (NHLBI) grant, R01-HL107612 (Yang and Wendt), and National Cancer Institute grants, R01-CA80127 (Yang), R01-CA84354 (Yang), R01-CA130996 (Lou), R01-CA108961 (Lou) and R01-CA148940 (Lou), and Mayo Clinic Foundation Funds (Yang and Lou), Mayo Clinic Cancer Center grant CA15083. We thank Dr. Thomas C. Smyrk (Mayo clinic) for IHC analysis. Jun She was supported by the National Natural Science Foundation for Young Scholars of China, No. 81200051 and Scientific Project for Fudan University, No. 20520133474. Bo Deng was supported by National Natural Science Foundation of China, No. 81101782 and Third Military Medical University MiaoPu project. Ola Larsson was supported by the Swedish Research Council and the Wallenbberg Academy Fellows Programme. Andrew Limper was supported by funds from the Annenberg Foundation. Biospeciens accessioning and processing, genotyping and RNA microarray analysis were supported partly by the Mayo Clinic Cancer Center grant CA15083.

PY - 2016

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N2 - 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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Multiple-level validation identifies PARK2 in the development of lung cancer and chronic obstructive pulmonary disease

Abstract

Bibliographical note

Keywords

UN SDGs

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