A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma.
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.
Tsai
Meng-Feng
MF
Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan.
Wang
Chi-Chung
CC
Chang
Gee-Chen
GC
Chen
Chih-Yi
CY
Chen
Hsuan-Yu
HY
Cheng
Chiou-Ling
CL
Yang
Yu-Ping
YP
Wu
Chun-Yi
CY
Shih
Fu-Yuan
FY
Liu
Chun-Chi
CC
Lin
Hsiu-Ping
HP
Jou
Yuh-Shan
YS
Lin
Shu-Chen
SC
Lin
Chung-Wu
CW
Chen
Wei J
WJ
Chan
Wing-Kai
WK
Chen
Jeremy J W
JJ
Yang
Pan-Chyr
PC
D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D015152:Blotting, Northern; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry* / Q000401:mortality*; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000032:analysis; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000032:analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D050956:HSP40 Heat-Shock Proteins / Q000032:analysis* / Q000235:genetics; D006801:Humans; D019656:Loss of Heterozygosity; D008175:Lung Neoplasms / Q000737:chemistry* / Q000401:mortality*; D018895:Microsatellite Repeats; D009364:Neoplasm Recurrence, Local / Q000453:epidemiology; D016017:Odds Ratio; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering; D015203:Reproducibility of Results; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000032:analysis; D016019:Survival Analysis; D014162:Transfection
D014408:Biomarkers, Tumor; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C494650:DNAJB4 protein, human; D050956:HSP40 Heat-Shock Proteins; D034741:RNA, Small Interfering; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D019938:Cyclin D1