© The Author 2006. Published by Oxford University Press.
ARTICLE |
A New Tumor Suppressor DnaJ-like Heat Shock Protein, HLJ1, and Survival of Patients With Non–Small-Cell Lung Carcinoma
Affiliations of authors: Department of Internal Medicine (MFT, CLC, YPY, FYS, PCY), Department of Pathology (CWL), Department of Medical Research (WKC), National Taiwan University Hospital, Taipei, Taiwan; NTU Center for Genomic Medicine, National Taiwan University, Taipei, Taiwan (MFT, CCW, HYC, CLC, YPY, CYW, FYS, HPL, WJC, JJWC, PCY); Department of Biotechnology, Chia-Nan University of Pharmacy and Science, Tainan, Taiwan (MFT); Division of Chest Medicine, Department of Internal Medicine (GCC), Division of Thoracic Surgery, Department of Surgery (CYC), Taichung Veterans General Hospital, Taichung, Taiwan; School of Medicine, China Medical University, Taichung, Taiwan (GCC); Graduate Institute of Epidemiology, National Taiwan University, Taipei, Taiwan (HYC, WJC); Department of Computer Science (CCL), Institutes of Biomedical Sciences and Molecular Biology (FYS, CCL, JJWC), National Chung-Hsing University, Taichung, Taiwan; Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan (YSJ, SCL, PCY)
Correspondence to: Jeremy J. W. Chen, PhD, Institutes of Biomedical Sciences and Molecular Biology, National Chung-Hsing University, Taichung, Taiwan (e-mail: jwchen{at}dragon.nchu.edu.tw) and Pan-Chyr Yang, MD, PhD, Department of Internal Medicine, National Taiwan University Hospital, No. 7 Chung-Shan South Road, Taipei 100, Taiwan (e-mail: pcyang{at}ha.mc.ntu.edu.tw).
Background: We previously identified DnaJ-like heat shock protein (HLJ1) as a gene associated with tumor invasion. Here, we investigated the clinical significance of HLJ1 expression in non–small-cell lung cancer (NSCLC) patients and its role in cancer progression. Methods: We induced HLJ1 overexpression or knockdown in human lung adenocarcinoma CL1–5 cells and analyzed cell proliferation, anchorage-independent growth, in vivo tumorigenesis, cell motility, invasion, and cell cycle progression. Expression of genes that act downstream of HLJ1 was examined by DNA microarray analysis, pathway analysis, and western blotting. We measured HLJ1 expression in tumors and adjacent normal tissues of 71 NSCLC patients by quantitative reverse transcription–polymerase chain reaction. Associations between HLJ1 expression and disease-free and overall survival were determined using the log-rank test and multivariable Cox proportional hazards regression analysis. Validation was performed in an independent cohort of 56 NSCLC patients. Loss of heterozygosity (LOH) mapping of the HLJ1 locus was analyzed in 48 paired microdissected NSCLC tumors. All statistical tests were two-sided. Results: HLJ1 expression inhibited lung cancer cell proliferation, anchorage-independent growth, tumorigenesis, cell motility, and invasion, and slowed cell cycle progression through a novel STAT1/P21WAF1 pathway that is independent of P53 and interferon. HLJ1 expression was lower in tumors than in adjacent normal tissue in 55 of 71 patients studied. NSCLC patients with high HLJI expressing tumors had reduced cancer recurrence (hazard ratio [HR] = 0.47; 95% confidence interval [CI] = 0.23 to 0.93; P = .03) and longer overall survival (HR = 0.38; 95% CI = 0.16 to 0.89; P = .03) than those with low-expressing tumors. Validation in the independent patient cohort confirmed the association between HLJ1 expression and patient outcome. LOH mapping revealed high frequencies (66.7% and 70.8%) of allelic loss and microsatellite instability (87.5% and 95.2%) of the HLJ1 locus at chromosome 1p31.1. Conclusions: HLJ1 is a novel tumor suppressor in NSCLC, and high HLJ1 expression is associated with reduced cancer recurrence and prolonged survival of NSCLC patients.
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- A New Tumor Suppressor Gene: Invasion, Metastasis, and Angiogenesis as Potential Key Targets
- Adriana Albini and Ulrich Pfeffer
J Natl Cancer Inst 2006 98: 800-801.[Extract] [Full Text] [PDF]
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