Tumorigenic role of orphan nuclear receptor NR0B1 in lung adenocarcinoma.
Cancer stem cells are a limited population of tumor cells that are thought to reconstitute whole tumors. The Hoechst dye exclusion assay revealed that tumors are composed of both a main population and a side population of cells, which are rich in cancer stem cells. NR0B1 is an orphan nuclear receptor that is expressed to a greater extent in the side population, as compared with the main population, of a lung adenocarcinoma cell line. In this study, we investigated the role of NR0B1 in lung adenocarcinoma cells. Reduction of NR0B1 expression levels in lung adenocarcinoma cell lines resulted in vulnerability to anti-cancer drugs and decreased abilities for invasion, in vitro colony formation, and tumorigenicity in non-obese diabetic/severe compromised immunodeficient mice. When 193 cases of lung adenocarcinoma were immunohistochemically examined, higher levels of NR0B1 expression correlated with higher rates of lymph node metastasis and recurrence. Multivariate analysis revealed high NR0B1 expression levels, stage of the disease, and size of tumor to be independent unfavorable prognostic factors for overall and disease-free survival rates. In clinical samples, NR0B1 expression levels inversely correlated to the proportion of methylated CpG sequences around the transcription initiation site of the NR0B1 gene, suggesting the epigenetic control of NR0B1 transcription in lung adenocarcinoma. In conclusion, NR0B1 might play a role in the malignant potential of lung adenocarcinoma.
Oda
Tomofumi
T
Department of Pathology, Graduate School of Medicine, Osaka University, Yamada-oka 2-2, Suita, Japan.
Tian
Tian
T
Inoue
Masayoshi
M
Ikeda
Jun-Ichiro
J
Qiu
Ying
Y
Okumura
Meinoshin
M
Aozasa
Katsuyuki
K
Morii
Eiichi
E
D000230:Adenocarcinoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D000818:Animals; D014408:Biomarkers, Tumor; D045744:Cell Line, Tumor; D057137:DAX-1 Orphan Nuclear Receptor / Q000096:biosynthesis* / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008207:Lymphatic Metastasis / Q000235:genetics; D008745:Methylation; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009361:Neoplasm Invasiveness / Q000235:genetics; D009368:Neoplasm Transplantation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012008:Recurrence; D014158:Transcription, Genetic
D014408:Biomarkers, Tumor; D057137:DAX-1 Orphan Nuclear Receptor; C539965:NR0B1 protein, human