Schizophrenia is a severe psychiatric disorder with a strong hereditary component that affects approximately 1% of the world's population. The disease is most likely caused by the altered expression of a number of genes that function at the level of biological pathways or gene networks. Transcription factors (TF) are indispensable regulators of gene expression. EGR3 is a TF associated with schizophrenia. In the current study, DNA microarray and ingenuity pathway analyses (IPA) demonstrated that EGR3 regulates Reelin signaling pathway in SH-SY5Y cells. ChIP and luciferase reporter studies confirmed that EGR3 directly binds to the promoter region of RELN thereby activating RELN expression. The expression of both EGR3 and RELN was decreased during neuronal differentiation induced by retinoic acid (RA) in SH-SY5Y cells, and EGR3 over-expression reduced neurite outgrowth which could be partially reversed by the knockdown of RELN. The expression levels of EGR3 and RELN in peripheral blood of subjects with schizophrenia were found to be down-regulated (compared with healthy controls), and were positively correlated. Furthermore, data mining from public databases revealed that the expression levels of EGR3 and RELN were presented a positive correlation in post-mortem brain tissue of subjects with schizophrenia. Taken together, this study suggests that EGR3 is a novel TF of the RELN gene and regulates neurite outgrowth via the Reelin signaling pathway. Our findings contribute to the understanding of the regulatory role of EGR3 in the pathophysiology and molecular mechanisms of schizophrenia, and potentially to the development of new therapies and diagnostic biomarkers for the disorder.
Androgen and androgen receptor (AR) play important roles in male spermatogenesis and fertility, yet detailed androgen/AR signals in Sertoli cells remain unclear.To identify AR target genes in Sertoli cells, we analyzed the gene expression profiles of testis between mice lacking AR in Sertoli cells (S-AR 2/y ) and their littermate wild-type (WT) mice.Digital gene expression analysis identified 2276 genes downregulated and 2865 genes upregulated in the S-AR 2/y mice testis compared to WT ones.To further nail down the difference within Sertoli cells, we first constructed Sertoli cell line TM4 with stably transfected AR (named as TM4/AR) and found androgens failed to transactivate AR in Sertoli TM4 and TM4/AR cells.Interestingly, additional transient transfection of AR-cDNA resulted in significant androgen responsiveness with TM4/AR cells showing 10 times more androgen sensitivity than TM4 cells.In the condition where maximal androgen response was demonstrated, we then analyzed gene expression and found the expression levels of 2313 genes were changed more than twofold by transient transfection of AR-cDNA in the presence of testosterone.Among these genes, 603 androgen-/ AR-regulated genes, including 164 upregulated and 439 downregulated, were found in both S-AR 2/y mice testis and TM4/AR cells.Using informatics analysis, the gene ontology was applied to analyze these androgen-/AR-regulated genes to predict the potential roles of androgen/AR in the process of spermatogenesis.Together, using gene analysis in both S-AR 2/y mice testis and TM4/AR cells may help us to better understand the androgen/AR signals in Sertoli cells and their influences in spermatogenesis.
Bladder cancer belongs to one of the most common cancers and is a leading cause of deaths in our society. Urothelial carcinoma of the bladder (UCB) is the main type of this cancer, and the estrogen receptors in UCB remain to be studied. Our experiment aimed to investigate the possible biological effect of 17 β -estradiol on human bladder-derived T24 carcinoma cells and to indicate its related mechanisms. T24 cells were treated with various doses of 17 β -estradiol, and cell proliferation was detected using MTT assays. 17 β -estradiol promoted T24 cell proliferation independent of ER β /GPR30-regulated EGFR-MAPK pathway, while it inhibited cell growth via GPR30. Furthermore, the expression levels of downstream genes ( c-FOS, BCL-2, and CYCLIN D1 ) were increased by 17 β -estradiol and this effect was independently associated with activity of the EGFR-MAPK pathway. The two estrogen receptors might be potential therapeutic targets for the treatment of bladder cancer.
Androgen receptor has a critical role in prostate cancer development and progression. Cell death via autophagy may also contribute to prostate cancer progression. We determined the role and regulatory effects of androgen receptor on the autophagy process of prostate cancer cells.Using a series of morphological approaches, such as transmission electron microscopy, monodansylcadaverine (Sigma®) and GFP-LC3 fluorescence microscopy assay, and Western blot we monitored the autophagic process in 3 pairs of prostate cancer cell lines to study the relationship to androgen receptor signals.Androgen receptor knockdown in androgen receptor positive cells, such as LNCaP or CWRrv1 human prostate cancer cells, led to increased autophagy. Adding functional androgen receptor to androgen receptor negative cells, such as PC3 human prostate cancer cells, resulted in decreased autophagy. This suggests that androgen receptor could have a negative role in regulating autophagy. Mechanism dissection indicated that androgen receptor might repress autophagy via modulation of p62 expression. A therapeutic approach of targeting androgen receptor to increase autophagy using the androgen receptor degradation enhancer ASC-J9® suppressed prostate cancer growth.Findings provide evidence that the androgen receptor might promote prostate cancer cell growth via autophagy down-regulation. Targeting the androgen receptor via ASC-J9 might lead to tumor suppression via the induction of autophagy. This may represent a new, potential therapeutic approach and mechanism for prostate cancer.
// Li Liu 1, 2, 4, * , Yuchen Liu 1, * , Xintao Zhang 1, * , Mingwei Chen 1 , Hanwei Wu 1 , Muqi Lin 1 , Yonghao Zhan 1, 4 , Chengle Zhuang 1, 4 , Junhao Lin 1, 4 , Jianfa Li 1, 4 , Wen Xu 1 , Xing Fu 1 , Qiaoxia Zhang 1 , Xiaojuan Sun 1 , Guoping Zhao 1, 5 , Weiren Huang 1, 3 1 Key Laboratory of Medical Reprogramming Technology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China 2 Urology Department, Qingyuan People's Hospital, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan, China 3 Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, National Urological Cancer Center, Beijing, China 4 Shantou University Medical College, Shantou, China 5 Shanghai-MOST Key Laboratory of Health and Disease Genomics, Chinese National Human Genome Center at Shanghai, Shanghai, China * These authors contributed equally to this work Correspondence to: Weiren Huang, email: pony8980@163.com Keywords: bladder cancer, ETS-1, oncogene, cell migration, cell invasion Received: August 21, 2015 Accepted: January 20, 2016 Published: February 04, 2016 ABSTRACT As one of the members of the ETS gene family, the transcription factor v-ets avian erythroblastosis virus E26 oncogene homolog 1 (ETS-1) plays key role in the regulation of physiological processes in normal cells and tumors. In this study, we aimed to investigate the relationship between the transcription factor ETS-1 and malignant phenotypes of bladder cancer. We demonstrated that ETS-1 was up-regulated in human bladder cancer tissue compared to paired normal bladder tissue. In order to evaluate the functional role of ETS-1 in human bladder cancer, vectors expressing ETS-1 shRNA and ETS-1 protein were constructed in vitro and transfected into the human bladder cancer T24 and 5637 cells. Our results showed that the transcription factor ETS-1 could promote cell migration and cell invasion in human bladder cancer, without affecting cell proliferation and apoptosis. In conclusion, ETS-1 plays oncogenic roles through inducing cell migration and invasion in human bladder cancer, and it can be used as a therapeutic target for treating human bladder cancer.
Previous studies have shown that nucleus pulposus (NP) cell death plays an extremely important role in the progress of intervertebral disc degeneration (IVDD). This research aimed to investigate the protective effect of the MLKL inhibitor necrosulfonamide (NSA) on human NP cells.We collected human NP tissues from the patients undergoing disc herniation operations and isolated NP cell from the samples. IL-1β (10 ng/ml) was used to establish a NP cells degenerated model. We analyzed the expression of caspase 3, caspase 8, RIPK1, RIPK 3, and MLKL in different degree of degenerate disc tissues. Cell viability was analyzed by the Cell Counting Kit-8 (CCK-8) assay. The expression levels of collagen Ⅱ, β-galactosidase (β-gal), caspase 3, caspase 8, RIPK1, RIPK 3, and MLKL, several inflammatory and anti-oxidant enzymes of different NP cell treat groups were detected by Western blotting, immunofluorescence staining, or RT-PCR. Flow cytometry was used to measure the ROS level and cell apoptosis.The data showed that expression of caspase 3, caspase 8, RIPK1, RIPK 3, and MLKL markedly increased in severely degenerated disc tissues. IL-1β promoted the cell death of NP cells, while NSA could reverse the effects of IL-1β. We found that NAS increased the antioxidant SOD1, SOD2, CAT, and GPX3 expression and suppressed oxidative stress in the disc. Moreover, MMP3, MMP10, IL-6, and TNF-α were significantly suppressed by the NSA.These results suggest that NSA prevented NP degradation via inhibiting apoptosis and necroptosis of NP cells. Besides, the protective function of antagonizing cell death may owe to the inflammation and oxidative stress suppression.
Background: The present retrospective study was designed to evaluate the relative diagnostic utility of breast-specific gamma imaging (BSGI) and breast magnetic resonance imaging (MRI) as means of evaluating female breast cancer patients in China. Methods: A total of 229 malignant breast cancer patients underwent ultrasound, mammography, BSGI, and MRI between January 2015 and December 2018 for initial tumor staging. Of these patients, 73 were subsequently treated via definitive breast surgery following neoadjuvant chemotherapy (NAC), of whom 17 exhibited a complete pathologic response (pCR) to NAC. Results: BSGI and MRI were associated with 76.8% (43/56) and 83.9% (47/56) sensitivity (BSGI vs. MRI, p = 0.341) values, respectively, as a means of detecting residual tumors following NAC, while both these approaches exhibited comparable specificity in this diagnostic context. The specificity of BSGI for detecting residual tumors following NAC was 70.6% (12/17), and that of MRI was 58.8% (10/17) (BSGI vs. MRI, p = 0.473). Conclusion: These results demonstrate that BSGI is a useful auxiliary approach to evaluating pCR to NAC treatment.
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