Journal of the National Cancer Institute Advance Access published online on November 11, 2008
JNCI Journal of the National Cancer Institute, doi:10.1093/jnci/djn379
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
© The Author 2008. Published by Oxford University Press.
ARTICLES |
Overexpression of OLC1, Cigarette Smoke, and Human Lung Tumorigenesis
Affiliations of authors: Department of Etiology and Carcinogenesis (JY, JM, HZ, WS, KZ, NH, GF, TX, YG, SC), Department of Pathology (DL), and Department of Chest Surgery (JH, YM), Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China; Chinese National Human Genome Center Beijing, Beijing, China (TS, XG, PG, DM); Department of Occupational Health and Toxicology, College of Public Health, Zhengzhou University, Zhengzhou, China (QZ); Human Disease Genomics Center, School of Basic Medical Science, Peking University Health Science Center, Beijing, China (DM)
Correspondence to: Shujun Cheng, Post Graduate; Yanning Gao, MD, PhD; and Dalong Ma, MD, PhD; Department of Chemical Etiology and Carcinogenesis, Cancer Institute & Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, PO Box 2258, Beijing 100021, People’s Republic of China (e-mail: Cheng, chengshj{at}263.net.cn; Gao, yngao{at}pubem.cicams.ac.cn; Ma, madl{at}bjmu.edu.cn)
Background: Exposure to cigarette smoke is a major risk factor for lung cancer, but how it induces cancer is unclear. The overexpressed in lung cancer 1 (OLC1) gene is one of 50 candidate lung cancer genes identified by suppression subtractive hybridization as having higher expression in squamous cell carcinoma (SCC) than normal lung epithelia.
Methods: We used immunohistochemistry (IHC) to measure OLC1 protein levels in primary lung cancer samples from 559 patients and used fluorescence in situ hybridization to measure OLC1 copy number in primary SCC samples from 23 patients. We compared OLC1 protein expression in SCC samples of 371 patients with and without a smoking history using the Pearson 
2 test. We assayed OLC1 protein levels by immunoblotting in H1299 human lung cancer cells, immortalized human bronchial epithelial cells, and primary cultured normal human bronchial epithelial cells that were treated with cigarette smoke condensate. We assayed tumor formation in athymic mice using NIH3T3 mouse fibroblast cells transfected with OLC1 (eight mice) and analyzed apoptosis and colony formation of H1299 and H520 lung cancer cells transfected with scrambled (negative) or OLC1 small interfering RNAs (siRNAs) (s1).
Results: OLC1 protein was overexpressed in 387 of 464 (83.4%) of primary lung cancers, as detected by IHC, and OLC1 was amplified in 14 of 23 (60%) of SCC samples. OLC1 protein overexpression was more common in SCC patients with a smoking history than those without (77.1% vs 45.8%, P < .001). In addition, cigarette smoke condensate increased OLC1 protein levels in H1299 cells, immortalized human bronchial epithelial cells, and primary cultured normal human bronchial epithelial cells. Overexpression of OLC1 induced tumor formation in athymic mice (control vs OLC1, 0% vs 100%). Knockdown of OLC1 increased apoptosis (mean percentage of apoptotic H1299 cells, s1 vs negative: 30.3% vs 6.4%, difference = 23.9%, 95% confidence interval [CI] = 19.1% to 28.5%, P = .002; mean percentage of apoptotic H520 cells, s1 vs negative: 21.6% vs 4.9%, difference = 16.7%, 95% CI = 10.6% to 22.8%, P = .007) and decreased colony formation (mean no. of colonies of H1299 cells transfected with siRNAs, negative vs s1: 84 vs 4, difference = 80, 95% CI = 71 to 88, P < .001; mean no. of colonies of H520 cells transfected with siRNAs, negative vs s1: 103 vs 24, difference = 79, 95% CI = 40 to 116, P = .005).
Conclusions: OLC1 is a candidate oncogene in lung cancer whose expression may be regulated by exposure to cigarette smoke.
| CONTEXT AND CAVEATS Prior knowledge Exposure to cigarette smoke increases the risk of lung cancer, but the mechanisms involved are unclear. Study design Lung cancer and normal lung tissues from patients and cell and animal models of lung cancer were used to examine the effect of overexpression of the gene overexpressed in lung cancer 1 (OLC1) on lung tumorigenesis and how cigarette smoke may be involved. Contribution OLC1 protein was overexpressed in the majority of the lung cancer tissues, and the OLC1 gene was amplified in a majority of lung squamous cell carcinoma samples. High OLC1 protein expression was associated with smoking history and increased expression was observed in cell lines after treatment with cigarette smoke condensate. Knockdown of OLC1 increased apoptosis and decreased colony formation in soft agar. Implications OLC1 is a candidate lung cancer oncogene whose expression may be increased by cigarette smoke. Limitations The association between OLC1 expression and smoking history was based on few samples from one group of patients. It is unknown how applicable the data generated from these models of lung cancer are to the human disease. From the Editors
|
Manuscript received January 31, 2008; revised August 25, 2008; accepted September 19, 2008.
Related Article in JNCI
CiteULike 
Connotea 
Del.icio.us What's this?
J Natl Cancer Inst 2008 100: 1561.
This article has been cited by other articles:
|
|
 |
|
  F. J. Kaye Defining a Candidate Lung Cancer Gene J Natl Cancer Inst, November 19, 2008; 100(22): 1564 - 1565. [Full Text] [PDF]
|
|