title: Clinical significance of steroid and xenobiotic receptor and its targeted gene CYP3A4 in human prostate cancer.
abstract: The steroid and xenobiotic receptor (SXR) regulates cytochrome P450 (CYP) enzymes, which are key inactivators of testosterone in the liver and prostate. In the present study, we investigated SXR expression in human prostate tissues. We determined SXR immunoreactivity using an anti-SXR antibody in benign (n = 78) and cancerous (n = 106) tissues obtained by radical prostatectomy. Stained slides were evaluated for the proportion and staining intensity of immunoreactive cells. Total immunoreactivity (IR) scores (range: 0-8) were calculated as the sum of the proportion and intensity scores. Associations between the clinicopathological features of the patients, SXR status, and CYP3A4 immunoreactivity were analyzed. Western blot analyses validated the specificity of the anti-SXR antibody in 293T cells transfected with pcDNA-FLAG-SXR. Positive (IR score: ≥ 2) nuclear SXR staining was observed in 91% (71/78) of benign foci and 47% (50/106) of cancerous lesions. Immunoreactivity scores were significantly lower in the cancerous lesions than in the benign foci (P < 0.0001). Clinicopathological analyses showed that cancer-specific survival in patients with high SXR IR scores (≥ 4) was significantly increased (P = 0.046). Combined data of present and previous studies showed that high IR scores for both the SXR and CYP3A4 correlated with significantly better cancer-specific survival rates in multivariate regression analyses (hazard ratio: 2.15, 95% confidence interval: 1.25-3.55, P = 0.007). We showed differential SXR expression in human prostate tissues. The high expression of the SXR and CYP3A4 is a strong prognostic indicator of favorable outcomes in prostate cancer, and could be a therapeutic target.
authors: Department of Urology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. FUJIMURAT-URO@h.u-tokyo.ac.jp
authors: Tetsuya
authors: T
authors: Fujimura
authors: Satoru
authors: S
authors: Takahashi
authors: Tomohiko
authors: T
authors: Urano
authors: Toshiya
authors: T
authors: Tanaka
authors: Weiguang
authors: W
authors: Zhang
authors: Kotaro
authors: K
authors: Azuma
authors: Kenich
authors: K
authors: Takayama
authors: Daisuke
authors: D
authors: Obinata
authors: Taro
authors: T
authors: Murata
authors: Kuniko
authors: K
authors: Horie-Inoue
authors: Tatsuhiko
authors: T
authors: Kodama
authors: Yasuyoshi
authors: Y
authors: Ouchi
authors: Yukio
authors: Y
authors: Homma
authors: Satoshi
authors: S
authors: Inoue
mesh_terms: D000368:Aged; D014408:Biomarkers, Tumor / Q000378:metabolism; D002460:Cell Line; D051544:Cytochrome P-450 CYP3A / Q000235:genetics* / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077297:Pregnane X Receptor; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D011987:Receptors, Steroid / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D000077297:Pregnane X Receptor; D011987:Receptors, Steroid; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human; D017430:Prostate-Specific Antigen