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Targeting of steroidogenic enzymes (e.g., abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here, we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote de novo androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors. Pharmacologic inhibition of LRH-1 activity attenuated LRH-1–mediated androgen deprivation and anti-androgen resistance of prostate cancer cells. Our findings not only demonstrate the significant role of LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management.Significance: These findings not only demonstrate the significant role of the nuclear receptor LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management. Cancer Res; 78(9); 2205–18. ©2018 AACR.

Supplementary Tables S1-S4

Supplementary Figures S1-S6

Centromere proteins (CENPs) are the main constituent proteins of kinetochore, which are essential for cell division. In recent years, several studies have revealed that several CENPs were aberrantly expressed in hepatocellular carcinoma (HCC). However, numerous centromere proteins have not been studied in HCC. In this study, we used databases of Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), the Kaplan-Meier Plotter, cBioPortal, the Human Protein Atlas (HPA), and TIMER (Tumor Immune Estimation Resource) and immunohistochemical staining of clinical specimens to investigate the expression of 15 major centromere proteins in HCC to evaluate their potential prognostic value. We found that the mRNA levels of 4 out of 15 centromere proteins (CENPL, CENPQ, CENPR, and CENPU) were significantly higher in HCC than in normal tissues, and their mRNA levels were associated with the tumor stages ( p values < 0.01). Patients with higher mRNA levels of CENPL had poorer overall survival, progression-free survival, relapse-free survival, and disease-specific survival ( p values < 0.05). Furthermore, the higher levels of CENPL mRNA were associated with worse overall survival in males without hepatitis virus infection ( p values < 0.05). The protein expression level of CENPL in human HCC tissue was higher than that in normal liver tissue. In addition, the expression of CENPL was positively correlated with the levels of the tumor-infiltrating lymphocytes. The results suggest that the high mRNA expression of CENPL may be a potential predictor of prognosis in HCC patients.

BACKGROUND High red cell distribution width (RDW) is correlated with poor prognosis in acute coronary syndromes (ACS), including ST-segment elevation myocardial infarction (STEMI). However, the association of red cell distribution width to erythrocyte count ratio (RER) with STEMI undergoing percutaneous coronary intervention (PCI) during hospitalization has not been investigated. Therefore, we performed a retrospective study to investigate whether RER is associated with STEMI patients after PCI during hospitalization. METHODS A total of 331 patients, who were hospitalized for STEMI and underwent PCI, were enrolled. Receiver operating characteristic curve (ROC) analyses were used to find the cutoff value of RER and classify the patients into two groups including higher RER group and lower RER group by cutoff value. Differences between measured parameters in higher RER and lower RER groups were analyzed by the Mann-Whitney U test. The evaluation correlation of RDW, red blood cell, and RER with major adverse cardiovascular events was determined by bivariate regression analysis. Univariate logistic regression analysis was used to determine the factors associated with adverse cardiovascular events during the hospitalization of STEMI patients. Multivariate logistic regression analysis was performed to evaluate the potential independent predictors of STEMI. RESULTS According to ROC analysis, the cutoff value of RER and RDW is 3.10 and 13.9, the sensitivity is 51% and 35%, the specificity is 76% and 80%, respectively. RER showed improved diagnostic capacity compared to RDW in correlation with adverse cardiovascular events during hospitalization in STEMI patients (p < 0.001). Compared with the lower RER group, the incidence of adverse cardiovascular events in STEMI patients is elevated in the higher RER group (75% vs. 64.5%, p < 0.05). Bivariate regression analysis indicated that RER and RDW showed a good correlation with adverse cardiovascular events, and the difference was statistically significant (R = 0.10 p < 0.05 vs. R = 0.05 p < 0.05). Univariate logistic regression analysis showed that age, heart rate, left ventricular ejection fraction, hyperlipidemia, RDW, mean platelet volume, total cholesterol, and RER were correlated with the occurrence of adverse cardiovascular events during the hospitalization of STEMI patients (p < 0.05). Multivariate logistic regression analysis demonstrated that RER could be an independent predictor of adverse cardiovascular events in STEMI patients (B: 0.574, OR: 1.776, 95% CI: 1.043 ~ 3.023, p < 0.05). CONCLUSIONS RER and RDW demonstrated good correlation with adverse cardiovascular events during hospitalization in STEMI patients. RER is a potential independent predictor of adverse cardiovascular events during hospitalization in STEMI patients.

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The treatment options of systemic lupus erythematosus (SLE) patients in active and inactive phases are very different clinically, and the prognosis of patients with active SLE is much worse than inactive patients. However, the present indicators for diagnosis of SLE in activity are limited and inefficient.Three hundred thirty patients with SLE were included. All patients are classified as SLEDAI (systemic lupus erythematosus disease activity index)4 as active and SLEDAI ≤ 4 as inactive. The linear correlation between variables was assessed by Pearson's correlation analysis. The difference between parameters in active and inactive patients was evaluated by the Mann-Whitney U test. The evaluation capacity of erythrocyte sedimenta-tion/red blood cell (ERR) and red blood cell/albumin ratio (RAR) on SLE activity was determined by bivariate regression analysis. Sensitivity and specificity are assessed by receiver operating characteristic curve (ROC).Compared with the inactive SLE, ESR (52.97 ± 35.66 vs. 32.38 ± 29.16 p0.001), ERR (15.40 ± 12.41 vs. 8.19 ± 8.10 p0.001) and RAR (0.13 ± 0.10 vs. 0.11 ± 0.20 p = 0.038) are all elevated in active SLE (52.97 ± 35.66 vs. 32.38 ±2 9.16 p0.001). ERR shows better correlation than RAR with ESR (p0.001 vs. p = 0.911). Patients with active SLE exhibited higher SLEDAI than those with inactive SLE (8.67 ± 2.67 vs. 3.27 ± 1.36, p0.001). According to ROC analysis, when ESR levels58.5 and ERR levels13.18, the sensitivity is 37.6% and 45.2%, the specificity is 83.0% and 83.2%.ESR and ERR are potential indicators for diagnosis of active and inactive SLE.

BACKGROUND We aimed to investigate the utility of albumin-to-glutamyltransferase ratio (AGR) as a new biomarker to distinguish hepatic carcinoma from hepatitis, as early disease diagnosis, prognosis or monitoring could improve patient management and outcomes. METHODS Clinical characteristics of 34 hepatitis (women 19), 88 cirrhosis (women 22) and 52 hepatic carcinoma (women 9) cases were retrospectively reviewed. Patients diagnosed with cirrhosis were classified by Child-Pugh score and the presence of ascites. The differences among groups were evaluated by the Kruskal-Wallis test and Mann-Whitney U. The linear correlation between variables was assessed by Spearman's correlation analysis. The diagnostic value of albumin-to-glutamyltransferase (AGR) was considered using receiver operating characteristic (ROC) curves. Multiple logistic regression analysis and univariate logistic regression analysis were used to identify AGR as an independent predictor in liver disease progression. RESULTS The significant differences among the hepatitis vs. cirrhosis vs. and hepatic carcinoma were AST (108.50 ± 184.00 vs. 38.00 ± 21.50 vs. 47.00 ± 71.00, p < 0.01), TP/AST (TAR, 0.67 ± 0.69 vs. 1.77 ± 0.87 vs. 1.36 ± 0.95, p < 0.01), and ALB/GGT (AGR, 0.32 ± 0.27 vs. 0.67 ± 0.43 vs. 0.20 ± 0.26, p < 0.05). At the same time, AST (32.00 ± 13.50 vs. 53.00 ± 23.00 vs. 114.50 ± 42.50, p < 0.05) and TAR (2.15 ± 0.72 vs. 1.28 ± 0.74 vs. 0.64 ± 0.39, p < 0.05) were higher but AGR (0.86 ± 0.54 vs. 0.46 ± 0.32 vs. 0.26 ± 0.22, p < 0.05) was lower in Child-Pugh class C group compared with group B and C. TAR (1.92 ± 0.73 vs. 0.98 ± 0.89, p < 0.01) and AGR (0.79 ± 0.52 vs. 0.46 ± 0.28, p < 0.05) were significantly elevated in the serum of cirrhosis with no ascites compared with the cirrhosis patients suffered from ascites, while AST (35.00 ± 14.50 vs. 63.00 ± 44.50, p < 0.01) was reduced in cirrhosis patients with no ascites. Furthermore, AST (r = 0.4490, p

Targeting of steroidogenic enzymes (e.g., abiraterone acetate targeting CYP17A1) has been developed as a novel therapeutic strategy against metastatic castration-resistant prostate cancer (CRPC). However, resistance to steroidal inhibitors inevitably develops in patients, the mechanisms of which remain largely unknown. Liver receptor homolog-1 (LRH-1, NR5A2) is a nuclear receptor, originally characterized as an important regulator of some liver-specific metabolic genes. Here, we report that LRH-1, which exhibited an increased expression pattern in high-grade prostate cancer and CRPC xenograft models, functions to promote de novo androgen biosynthesis via its direct transactivation of several key steroidogenic enzyme genes, elevating intratumoral androgen levels and reactivating AR signaling in CRPC xenografts as well as abiraterone-treated CRPC tumors. Pharmacologic inhibition of LRH-1 activity attenuated LRH-1–mediated androgen deprivation and anti-androgen resistance of prostate cancer cells. Our findings not only demonstrate the significant role of LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management. Significance: These findings not only demonstrate the significant role of the nuclear receptor LRH-1 in the promotion of intratumoral androgen biosynthesis in CRPC via its direct transcriptional control of steroidogenesis, but also suggest targeting LRH-1 could be a potential therapeutic strategy for CRPC management. Cancer Res; 78(9); 2205–18. ©2018 AACR.

The metastatic castration-resistant prostate cancer (CRPC) is a lethal form of prostate cancer, in which the expression of androgen receptor (AR) is highly heterogeneous. Indeed, lower AR expression and attenuated AR signature activity is shown in CRPC tissues, especially in the subset of neuroendocrine prostate cancer (NEPC) and prostate cancer stem-like cells (PCSCs). However, the significance of AR downregulation in androgen insensitivity and de-differentiation of tumor cells in CRPC is poorly understood and much neglected. Our previous study shows that the orphan nuclear receptor TLX (NR2E1), which is upregulated in prostate cancer, plays an oncogenic role in prostate carcinogenesis by suppressing oncogene-induced senescence. In the present study, we further established that TLX exhibited an increased expression in metastatic CRPC. Further analyses showed that overexpression of TLX could confer resistance to androgen deprivation and anti-androgen in androgen-dependent prostate cancer cells in vitro and in vivo, whereas knockdown of endogenous TLX could potentiate the sensitivity to androgen deprivation and anti-androgen in prostate cancer cells. Our study revealed that the TLX-induced resistance to androgen deprivation and anti-androgen was mediated through its direct suppression of AR gene transcription and signaling in both androgen-stimulated and -unstimulated prostate cancer cells. We also characterized that TLX could bind directly to AR promoter and repress AR transcription by recruitment of histone modifiers, including HDAC1, HDAC3, and LSD1. Together, our present study shows, for the first time, that TLX can contribute to androgen insensitivity in CRPC via repression of AR gene transcription and signaling, and also implicates that targeting the druggable TLX may have a potential therapeutic significance in CRPC management, particularly in NEPC and PCSCs.

Lijia Xiao,1,2,* Yuliang Wang,3,* Weicheng Liang,3 Liping Liu,4 Nannan Pan,1 Huimin Deng,1 Luqian Li,1 Chang Zou,5 Franky Leung Chan,3 Yiwen Zhou1 1Department of Clinical Laboratory Medicine, Shenzhen Hospital, Southern Medical University, Shenzhen, China; 2Department of Clinical Laboratory, Nanshan Affiliated Hospital of Guangdong Medical University, Shenzhen, China; 3School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong, China; 4Department of Hepatobiliary and Pancreatic Surgery, The Second Clinical Medical College (Shenzhen People’s Hospital), Jinan University, Shenzhen, China; 5Clinical Medicine Research Center, Shenzhen Public Service Platform of Precision Medicine and Molecular Diagnosis on Tumor, The Second Clinical Medical College (Shenzhen People’s Hospital), Jinan University, Shenzhen, China *These authors contributed equally to this work Background: To explore potential therapeutic target is one of the areas of great interest in both clinical and basic hepatocellular carcinoma (HCC) studies. Nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) is proved to play a positive role in several cancers including breast cancer, pancreatic cancer and intestinal cancer in recent years. However, the exact role of LRH-1 in the development and progression of HCC is not fully elucidated. Methods: The LRH-1 expression level in HCC clinical samples was examined by immunohistochemistry (IHC). Stable LRH-1-suppressed HepG2 clones (HepG2LRH-1/-) were generated by transcription activator-like effector nucleases (TALENs) and both in vitro and in vivo experiments were conducted. Results: We confirmed that LRH-1 showed an increased expression pattern in HCC clinical samples. Our in vitro and in vivo results indicated that suppression of LRH-1 in HepG2 significantly attenuated its proliferation rate and tumorigenic capacity. Gene expression microarray analysis indicated that LRH-1mostly regulated gene expression involved in cell cycle. In addition, our gain-of-function experiments indicated that ectopic expression of LRH-1 dramatically induced the mRNA and protein levels of c-myc and cyclin E1, while attenuating the expression of p21. Conclusion: Our results suggest that LRH-1 might be a potential therapeutic target for clinical HCC treatment. Keywords: LRH-1, HCC, c-myc, p21, cyclin E1

Oncogene-induced senescence is an important tumour-suppressing mechanism to prevent both premalignant transformation and cancer progression. Overcoming this process is a critical step in early cancer development. The druggable orphan nuclear receptor TLX (NR2E1) is characterized as an important regulator of neural stem cells and is also implicated in the development of some brain tumours. However, its exact functional roles in cancer growth regulation still remain unclear. Here we report that TLX can act as a promoter of tumourigenesis in prostate cancer by suppressing oncogene-induced senescence. We determined that TLX exhibited an increased expression in high-grade prostate cancer tissues and many prostate cancer cell lines. Functional studies revealed that TLX could perform an oncogenic function in prostate cancer cells, as its knockdown triggered cellular senescence and cell growth arrest in vitro and in vivo, whereas its over-expression promoted the malignant growth of prostate cancer cells. Furthermore, enhancement of TLX activity, by either ectopic expression or ligand stimulation, could potently prevent doxorubicin-induced senescence in prostate cancer cells and also allow prostatic epithelial cells to escape oncogene-induced senescence induced either by activated oncogene H-Ras(G12V) or knockdown of tumour suppressor PTEN, via a mechanism of direct but differential transcriptional regulation of two senescence-associated genes, repression of CDKN1A and transactivation of SIRT1. Together, our present study shows, for the first time, that TLX may play an important role in prostate carcinogenesis through its suppression of oncogene-induced senescence, and also suggests that targeting the senescence-regulatory TLX is of potential therapeutic significance in prostate cancer.

Reverse non-equilibrium (RNE) method is applied to investigate the rheological properties of surfactant solutions by using dissipative particle dynamics algorithm. Results show that the surfactant solutions exhibit a shear-thinning behaviour. With the strengthening of shear, the worm-like micelles are gradually oriented in the x direction and then broken up into small spherical micelles. The process is also shown by the decrease of viscosity, which starts quickly, levels off for moderate shear rates and speeds up again over a critical value. We find that this critical value is independent of surfactant concentration. Compared with the shear flow method, the RNE method is credible for moderate shear rate and has more computational efficiency.

Post-cataract surgery fibrosis in the lens capsule is caused by epithelial to mesenchymal transition (EMT) of the lens epithelium. Mammalian target of rapamycin (mTOR) has been demonstrated to be a key regulator of EMT. The aim of this study was to investigate the role of mTOR in transforming growth factor β2 (TGF-β2)-induced EMT in human lens epithelial cells (HLECs). Human lens epithelial B-3 (HLEB-3) cells were cultured with 10 ng/ml TGF-β2 for different periods of time. The expression of E-cadherin, connexin 43, fibronectin and α-smooth muscle actin (α-SMA), and activation of mTOR were determined by Western blots. Cell migration was assessed by wound healing assay. An inhibition test was performed using two kinds of mTOR inhibitors. E-cadherin and connexin 43 expressions were suppressed, whereas fibronectin and α-SMA expressions were increased in HLEB-3 cells after treatment with TGF-β2. mTOR was activated during the TGF-β2-induced EMT in a time-dependent manner. Rapamycin or Ku-0063794 with 100 nM was able to inhibit the phosphorylation of mTOR and impaired EMT induced by TGF-β2. Cell motility enhanced by TGF-β2 for 24 h was attenuated by both rapamycin and Ku-0063794. mTOR is activated during TGF-β2-induced EMT in HLECs, suggesting that it is involved in the regulation of TGF-β2-induced EMT and may contribute to the development of posterior capsule opacification.

Purpose C-end rule (CendR) peptides are found to enhance the penetration of chemotherapeutic agents into tumor cells, while GX1 is a peptide that homes to gastric cancer (GC) vasculature. This study aimed to synthesize a novel peptide GX1-RPAKPAR (GXC) and to explore the effect of GXC on sensitizing GC cells to chemotherapeutic agents. Materials and methods Intracellular Adriamycin concentration analysis was applied to conform whether GXC peptide increases the penetration of chemotherapeutic agents into GC cells in vitro. The effect of GXC peptide on sensitizing GC cells to chemotherapeutics was validated by apoptosis assay and in vitro/vivo drug sensitivity assay. The specificity of GXC to GC tissue was validated by ex vivo fluorescence imaging. Results In vitro, administration of GXC significantly increased Adriamycin concentrations inside SGC-7901 cells, and enhanced the efficacy of chemotherapeutic agents by decreasing the IC₅₀ value. In vivo, FITC-GXC specifically accumulated in GC tissue. Moreover, systemic co-injection with GXC peptide and Adriamycin statistically improved the therapeutic efficacy in SGC-7901 xenograft models, surprisingly, without obviously increasing side effects. Conclusion These results demonstrated that co-administration of the novel peptide GXC with chemotherapeutic agents may be a potential way to enhance the efficacy of anticancer drugs in GC treatment.

The present study aimed to investigate whether the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway is involved in the transforming growth factor β2 (TGF-β2)-induced epithelial-mesenchymal transition (EMT) in human lens epithelial (HLE) cells. HLEB-3 cells were cultured and stimulated with 10 ng/ml TGF-β2 for 24 h. Western blotting was then performed to analyze the expression levels of connexin 43 and fibronectin, and the activities of Akt and mTOR. Confocal cell immunofluorescence was used to observe the expression of phosphorylated (p)-Akt. The toxicity of 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) was assessed using a Cell Counting Kit-8 assay, and inhibition investigations were performed using a PI3K inhibitor. The expression of connexin 43 was suppressed and the expression of fibronectin was increased when the cells were stimulated with 10 ng/ml TGF-β2 for 24 h. In addition, Akt and mTOR were activated during TGF-β2-induced EMT. Treatment of with LY294002 (20 µM) inhibited the activation of Akt and mTOR and effectively prevented TGF-β2-induced EMT in the HLECs. Therefore, the results of the present study indicated that TGF-β2 induces EMT by activating the PI3K/Akt/mTOR signaling pathway in cultured HLECs.

To develop optimal therapeutics is one of the hotspots in both clinical and basic melanoma studies. Previous studies indicate that fibroblast growth factors (b-FGF/FGF-2), an angiogenesis inducer beyond VEGF, might be a potential drug target in melanoma. As a novel anti-angiogenesis peptide drug, Endostar has shown promising therapeutic efficacy in non-small cell lung cancer. However, the effect of Endostar on b-FGF-induced angiogenesis in melanoma is unraveled. To this end, both in vivo and in vitro experiments were conducted and it was found that treatment of Endostar could inhibit tumor growth, which was accompanied by decreased micro-vessel density and serum b-FGF levels in a mouse melanoma model. In addition, treatment with Endostar in blood vessel endothelial cells could reduce their proliferation, cell migration and tube formation capacity in a dosage-dependent manner. Moreover, treatment of Endostar could also attenuate b-FGF-activated phosphorylation of p38 and ERK1/2 in HUVECs. These findings indicate that Endostar might exert its anti-tumor effect via suppressing b-FGF-induced angiogenesis and b-FGF-activated MAPK signaling pathway, suggesting that Endostar might be a potential choice for clinical melanoma treatment.

Post-cataract surgery fibrosis in the lens capsule is caused by epithelial to mesenchymal transition (EMT) of the lens epithelium. Mammalian target of rapamycin (mTOR) has been demonstrated to be a key regulator of EMT. The aim of this study was to investigate the role of mTOR in transforming growth factor β₂ (TGF-β₂)-induced EMT in human lens epithelial cells (HLECs).Human lens epithelial B-3 (HLEB-3) cells were cultured with 10 ng/ml TGF-β₂ for different periods of time. The expression of E-cadherin, connexin 43, fibronectin and α-smooth muscle actin (α-SMA), and activation of mTOR were determined by Western blots. Cell migration was assessed by wound healing assay. An inhibition test was performed using two kinds of mTOR inhibitors.E-cadherin and connexin 43 expressions were suppressed, whereas fibronectin and α-SMA expressions were increased in HLEB-3 cells after treatment with TGF-β₂. mTOR was activated during the TGF-β₂-induced EMT in a time-dependent manner. Rapamycin or Ku-0063794 with 100 nM was able to inhibit the phosphorylation of mTOR and impaired EMT induced by TGF-β₂. Cell motility enhanced by TGF-β₂ for 24 h was attenuated by both rapamycin and Ku-0063794.mTOR is activated during TGF-β₂-induced EMT in HLECs, suggesting that it is involved in the regulation of TGF-β₂-induced EMT and may contribute to the development of posterior capsule opacification.

Inflammatory pathological injury caused by Chlamydia trachomatis persistent infection could lead to a variety of urogenital tract diseases. By comparing the cytokine production and PRR (pattern recognition receptor) expression between cell models with acute or persistent C. trachomatis infection, our data supported that persistent infection of C. trachomatis led to abnormal activation of toll-like receptor (TLR)2/4 signaling pathway and elevated IL-1α and IL-6 production, which was mediated by signal transducer and activator of transcription3 (STAT3). Studying the effects of abnormal activation of TLR signaling pathway in the cells with C. trachomatis persistent infection could provide new hints for chronic infection treatment and an important experimental basis for understanding the pathogenesis of C. trachomatis persistent infection.

The advanced development of castration-resistant prostate cancer (CRPC) in patients upon androgen-deprivation therapy is generally believed to be mostly mediated by reactivation of androgen receptor (AR) signaling or its bypass with mechanisms involved, including clonal selection of androgen-independent or stem cell-like cell populations, AR hypersensitivity due to AR overexpression, and ligand promiscuity or independence by AR mutations, intratumoral conversion of adrenal androgens to high affinity AR ligands. Besides, the de novo steroid synthesis from cholesterol in CRPC has also been proposed. In this study, we found that the nuclear receptor liver receptor homolog-1 (LRH-1) might contribute to the CRPC growth or de novo steroid synthesis in prostate cancer cells through its positive regulation on expression of several critical enzymes in steroidogenesis, including CYP17A1, HSD3B1, HSD3B2 and StAR. Functional analyses showed that overexpression of LRH-1 could induce higher resistance to antiandrogen bicalutamide and steroid-depleted culture condition in AR-positive androgen-sensitive (LNCaP) but not in AR-negative androgen-insensitive (DU145) prostate cancer cells. In vivo tumorigenicity study showed that LNCaP-LRH-1 cells grew more aggressively in castrated or intact SCID mice, contrary to LNCaP-vector control cells that did not grow in castrated mice. Importantly, liquid chromatography-tandem mass spectrometry showed that intratumoral androgen concentrations (testosterone and DHT) were significantly higher in tumors formed by LNCaP-LRH-1 cells than those by LNCaP-vector control cells. Treatment of LNCaP-LRH-1 cells with a CYP17A1 inhibitor abiraterone could restore their sensitivity to bicalutamide and steroid-depleted culture condition. Gene knockdown of endogenous LRH-1 in AR-positive VCaP prostate cancer cells could not only suppress the mRNA expression of steroidogenic enzymes but also enhance their sensitivity to antiandrogen. Together, our results indicated that LRH-1 might play a regulatory role in advanced castration-resistant growth of prostate cancer via positive control on de novo steroid synthesis in prostate cancer cells. (This work was supported by a Direct Grant for Research 2011/2012 and a RGC-GRF grant 2009/2010) Citation Format: Lijia Xiao, Shan Yu, Wendy W.L. Hsiao, Franky Leung Chan. Regulatory role of an orphan nuclear receptor LRH-1 in castration-resistant growth of prostate cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4771. doi:10.1158/1538-7445.AM2013-4771