Haplotype and cell proliferation analyses of candidate lung cancer susceptibility genes on chromosome 15q24-25.1.
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.
Washington University, St. Louis, Missouri, USA.
Yan
Y
Liu
Pengyuan
P
Liu
Weidong
W
Wen
Michael A
MA
James
Yian
Y
Wang
Joan E
JE
Bailey-Wilson
Christopher I
CI
Amos
Susan M
SM
Pinney
Ping
P
Yang
Mariza
M
de Andrade
Gloria M
GM
Petersen
Jonathan S
JS
Wiest
Pamela R
PR
Fain
Ann G
AG
Schwartz
Adi
A
Gazdar
Colette
C
Gaba
Henry
H
Rothschild
Diptasri
D
Mandal
Elena
E
Kupert
Juwon
J
Lee
Daniela
D
Seminara
John
J
Minna
Marshall W
MW
Anderson
Ming
M
You
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics*; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D002884:Chromosomes, Human, Pair 15; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D020161:Physical Chromosome Mapping; D046988:Proteasome Endopeptidase Complex / Q000235:genetics
D046988:Proteasome Endopeptidase Complex