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Haplotype and cell proliferation analyses of candidate lung cancer susceptibility genes on chromosome 15q24-25.1. Cancer Res 2009 Oct 01;69(19):7844-50 PMID: 19789337 PMCID: PMC2846106

Pubmed ID

19789337

DOI

10.1158/0008-5472.CAN-09-1833

Abstract

Recent genome-wide association studies have linked the chromosome 15q24-25.1 locus to nicotine addiction and lung cancer susceptibility. To refine the 15q24-25.1 locus, we performed a haplotype-based association analysis of 194 familial lung cases and 219 cancer-free controls from the Genetic Epidemiology of Lung Cancer Consortium (GELCC) collection, and used proliferation and apoptosis analyses to determine which gene(s) in the 15q24-25.1 locus mediates effects on lung cancer cell growth in vitro. We identified two distinct subregions, hapL (P = 3.20 x 10(-6)) and hapN (P = 1.51 x 10(-6)), which were significantly associated with familial lung cancer. hapL encompasses IREB2, LOC123688, and PSMA4, and hapN encompasses the three nicotinic acetylcholine receptor subunit genes CHRNA5, CHRNA3, and CHRNB4. Examination of the genes around hapL revealed that PSMA4 plays a role in promoting cancer cell proliferation. PSMA4 mRNA levels were increased in lung tumors compared with normal lung tissues. Down-regulation of PSMA4 expression decreased proteasome activity and induced apoptosis. Proteasome dysfunction leads to many diseases including cancer, and drugs that inhibit proteasome activity show promise as a form of cancer treatment. Genes around hapN were also investigated, but did not show any direct effect on lung cancer cell proliferation. We concluded that PSMA4 is a strong candidate mediator of lung cancer cell growth, and may directly affect lung cancer susceptibility through its modulation of cell proliferation and apoptosis.

Author List

Liu Y, Liu P, Wen W, James MA, Wang Y, Bailey-Wilson JE, Amos CI, Pinney SM, Yang P, de Andrade M, Petersen GM, Wiest JS, Fain PR, Schwartz AG, Gazdar A, Gaba C, Rothschild H, Mandal D, Kupert E, Lee J, Seminara D, Minna J, Anderson MW, You M

Authors

Michael James PhD Assistant Professor in the Surgery department at Medical College of Wisconsin
Pengyuan Liu PhD Adjunct Associate Professor in the Physiology department at Medical College of Wisconsin
Yian Wang MD, PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin
Ming You MD, PhD Associate Provost, Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




Scopus

2-s2.0-70350215708   35 Citations

MESH terms used to index this publication - Major topics in bold

Carcinoma, Non-Small-Cell Lung
Cell Growth Processes
Cell Line, Tumor
Chromosomes, Human, Pair 15
Genetic Predisposition to Disease
Haplotypes
Humans
Lung Neoplasms
Physical Chromosome Mapping
Proteasome Endopeptidase Complex
jenkins-FCD Prod-353 9ccd8489072cb19f5b9f808bb23ed672c582f41e