NR1H3 Expression is a Prognostic Factor of Overall Survival for Patients with Muscle-Invasive Bladder Cancer
JOURNAL OF CANCER
Authors: Wu, Junlong; Wan, Fangning; Sheng, Haoyue; Shi, Guohai; Shen, Yijun; Lin, Guowen; Dai, Bo; Zhu, Yiping; Ye, Dingwei
Abstract
Background: Nuclear receptors (NRs) are a class of transcription factors that regulate many cellular functions through manipulation of gene expression and also play important roles in tumorigenesis, proliferation, progression and prognosis in various kinds of cancers according to recent studies. This work aimed to determine the predictive ability of NRs in muscle-invasive bladder cancer (MIBC). Patients and methods: A total of 308 MIBC patients with complete clinicopathological and RNASeq data from The Cancer Genome Atlas (TCGA) cohort were collected for filtration. Genes showed clear correlations with overall survival (OS) and recurrence free survival (RFS) were further validated in 123 MIBC patients recruited consecutively from 2008 to 2012 in Fudan University Shanghai Cancer Center (FUSCC) cohort. Cox proportional hazards regression model and Kaplan-Meier plot were used to assess the relative factors. Results: In TCGA cohort, we found that high NR1H3 (HR=0.779, 95% CI: 0.634-0.957), NR2C1 (HR=0.673, 95% CI: 0.458-0.989) and NR2F6 (HR=0.750, 95% CI: 0.574-0.980) expressions were independent factors of favorable OS, while only low NR1H3 (log-rank test, P=0.0076) and NR2F6 (log-rank test, P=0.0395) expressions had the ability to predict poor prognosis for RFS. Further, in FUSCC validating cohort, we confirmed that low NR1H3 expression level was independent factor of poor OS (HR=1.295, 95% CI: 1.064-1.576) and it had the ability to predict poor RFS (log-rank test, P=0.0059). Conclusions: Low NR1H3 expression level is an independent prognostic factor of poor OS, and can also predict worse RFS in MIBC patients. Our "TCGA filtrating and local database validating" model can help reveal more prognostic biomarkers and cast a new light in understanding certain gene function in MIBC.
Multiple noncoding exons 1 of nuclear receptors NR4A family (nerve growth factor-induced clone B, Nur-related factor 1 and neuron-derived orphan receptor 1) and NR5A1 (steroidogenic factor 1) in human cardiovascular and adrenal tissues
JOURNAL OF HYPERTENSION
Authors: Demura, Masashi; Wang, Fen; Yoneda, Takashi; Karashima, Shigehiro; Mori, Shunsuke; Oe, Masashi; Kometani, Mitsuhiro; Sawamura, Toshitaka; Cheng, Yuan; Maeda, Yuji; Namiki, Mikio; Ino, Hidekazu; Fujino, Noboru; Uchiyama, Katsuharu; Tsubokawa, Toshinari; Yamagishi, Masakazu; Nakamura, Yasuhiro; Ono, Katsuhiko; Sasano, Hironobu; Demura, Yoshiki; Takeda, Yoshiyu
Abstract
Objective Nuclear receptors are involved in a wide variety of functions, including aldosteronogenesis. Nuclear receptor families NR4A [nerve growth factor-induced clone B (NGFIB), Nur-related factor 1 (nURR1) and neuron-derived orphan receptor 1 (NOR1)] and NR2F [chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TFI), COUP-TFII and NR2F6) activate, whereas NR5A1 [steroidogenic factor 1 (SF1)] represses CYP11B2 (aldosterone synthase) gene transcription. The present study was undertaken to elucidate the mechanism of differential regulation of nuclear receptors between cardiovascular and adrenal tissues. Methods We collected tissues of artery (n=9), cardiomyopathy muscle (n=9), heart muscle (noncardiomyopathy) (n=6), adrenal gland (n=9) and aldosterone-producing adenoma (APA) (n=9). 5'-rapid amplification of cDNA ends (RACE) identified transcription start sites. Multiplex reverse-transcription PCR (RT-PCR) determined use of alternative noncoding exons 1 (ANEs). Results In adrenocortical H295R cells, angiotensin II, KCl or cAMP, all stimulated CYP11B2 transcription and NR4A was upregulated, whereas NR2F and NR5A1 were downregulated. 5'-RACE and RT-PCR revealed four ANEs of NGFIB (NR4A1), three of NURR1 (NR4A2), two of NOR1 (NR4A3) and two of SF1 (NR5A1) in cardiovascular and adrenal tissues. Quantitative multiplex RT-PCR showed NR4A and NR5A1 differentially employed multiple ANEs in a tissue-specific manner. The use of ANEs of NGFIB and NURR1 was significantly different between APA and artery. Changes in use of ANEs of NGFIB and NOR1 were observed between cardiomyopathy and noncardiomyopathy. The NR4A mRNA levels in artery were high compared with cardiac and adrenal tissues, whereas the NR5A1 mRNA level in adrenal tissues was extremely high compared with cardiovascular tissues. Conclusion NR4A and NR5A1 genes are complex in terms of alternative promoter use. The use of ANEs may be associated with the pathophysiology of the heart and adrenal gland. J Hypertens 29: 1185-1195 (C) 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.