A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma
Journal
Journal of the National Cancer Institute
Journal Volume
98
Journal Issue
12
Pages
825-838
Date Issued
2006
Author(s)
Tsai M.-F.
Wang C.-C.
Chang G.-C.
Chen C.-Y.
Chen H.-Y.
Cheng C.-L.
Yang Y.-P.
Wu C.-Y.
Shih F.-Y.
Liu C.-C.
Lin H.-P.
Jou Y.-S.
Lin S.-C.
Chan W.-K.
Chen J.J.W.
Abstract
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/P21 WAF1 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. ? 2006 Oxford University Press.
SDGs
Other Subjects
cyclin dependent kinase inhibitor 1; DnaJ like heat shock protein; interferon; protein p53; STAT1 protein; tumor suppressor protein; unclassified drug; animal experiment; animal model; article; cancer growth; cancer recurrence; cancer survival; carcinoma cell; cell cycle progression; cell growth; cell invasion; cell motility; cell proliferation; chromosome 1p; confidence interval; controlled study; DNA microarray; gene locus; gene mapping; gene overexpression; heterozygosity loss; human; human cell; human tissue; in vivo study; log rank test; lung adenocarcinoma; lung non small cell cancer; major clinical study; microsatellite instability; mouse; nonhuman; nucleotide sequence; priority journal; proportional hazards model; reverse transcription polymerase chain reaction; validation process; Western blotting; Blotting, Northern; Blotting, Western; Carcinoma, Non-Small-Cell Lung; Cell Cycle; Cell Line, Tumor; Cell Movement; Cell Proliferation; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p21; Disease Progression; Disease-Free Survival; Flow Cytometry; Gene Expression Regulation, Neoplastic; HSP40 Heat-Shock Proteins; Humans; Loss of Heterozygosity; Lung Neoplasms; Microsatellite Repeats; Neoplasm Recurrence, Local; Odds Ratio; Oligonucleotide Array Sequence Analysis; Reproducibility of Results; Reverse Transcriptase Polymerase Chain Reaction; RNA, Small Interfering; STAT1 Transcription Factor; Survival Analysis; Transfection; Tumor Markers, Biological
Type
journal article