Jab1 Silencing Inhibits Proliferation and Sensitizes to Cisplatin in Biliary Tract Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Jab1 is a coactivator of c-Jun that enhances the transcriptional function of c-Jun. Jab1 is frequently overexpressed in various cancers and is associatedwith poor prognosis of cancer patients. Thus, Jab1 could be a potential therapeutic target in cancer. However, the role of Jab1 in biliary tract cancer (BTC) has not been studied. MATERIALS AND METHODS: We performed in vitro and in vivo experiments to evaluate the therapeutic potential ofJab1 inhibition in BTC. RESULTS: Among 8 BTC cell lines, many showed higher Jab1 expression levels. In addition, Jab1 silencing by siRNA increased p27 expression levels. SNU478 and HuCCT-1 cells exhibited profound Jab1 knockdown and increased p27 expression by Jab1-specific siRNA transfection. Jab1 silencing induced anti-proliferative and anti-migratory effects and resulted in G1 cell cycle arrest in SNU478 and HuCCT-1 cells. In addition, Jab1 silencing potentiated the anti-proliferative and anti-migratory effects of cisplatin by increasing DNA damage. Interestingly,Jab1 knockdown increased PTEN protein half-life, resulting in increased PTEN expression. In the HuCCT-1 mouse xenograft model, stable knockdown of Jab1 by shRNA also showed anti-proliferative effects in vivo, with decreased Ki-67 expression and AKT phosphorylation and increased Terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling and p27 expression. CONCLUSION: Jab1 knockdown demonstrated anti-proliferative and anti-migratory effects in BTC cells by increasing DNA damage and stabilizing PTEN, resulting in G1 cell cycle arrest. In addition, Jab1 silencing potentiated the anti-proliferative effects of cisplatin. Our data suggest that Jab1 may be a potential therapeutic target in BTC that is worthy of further investigations.

Relationship between TRX1 and JAB1 in acute myelogenous leukemia / 西安交通大学学报(医学版)

ABSTRACT:Objective To detect the expressions of thioredoxin (TRX1)and c-jun-activation-domain binding protein-1 (JAB1)in patients with acute myelogenous leukemia (AML)and healthy controls,and measure the TRX1 level in AML patients at different stages for evaluating its clinical significance.Methods The expressions of TRX1 and JAB1 in leukemia samples were analyzed by RT-PCR and Western blot at mRNA and protein levels, respectively.The correlation between TRX1 and JAB1,and the relationship between the gene expression and peripheral blood leukocytes count were also analyzed.Furthermore,serum TRX1 was measured by ELISA.Results TRX1 and JAB1 expressions at both mRNA and protein levels were obviously upregulated in leukemia patients (P<0.05). TRX1 was positively related to JAB1 in both newly diagnosed and recurrent AML patients.And high levels of TRX1 and JAB1 expressions were associated with white blood cell (WBC)counts in AML patients (P<0.05).Moreover, abundance of TRX1 in serum was significantly greater in AML patients,especially in the patients with recurrent AML,than in healthy donors (P<0.05).Conclusion There is a positive correlation between the expressions of TRX1 and JAB1 ,which is closely related to the occurrence and progression of AML.

The Anti-Tumor Effect and Mechanism of Curcumin in Pancreatic Cancer / 天津医药

Objective To investigate the anti-tumor effect and mechanism of curcumin in pancreatic cancer (PC). Methods Smad4 and Jab1 expressions were detected by immunohistochemistry in tumor tissues and pericarcinomatous tis?sue from 35 PC cases, and the correlation of Smad4 and Jab1 were analyzed based on the percentage of positive staining in?tissues from 21 random selected PC cases. The effect of curcumin on expressions of tumor suppressors p53, Smad4 and cell cycle inhibitor p27 were examined by Western Blotting after human pancreatic cancer cell line PANC-1 were divided into PANC-1 control group (no treatments were given) and PANC-1 curcumin group (treated with cell culture medium containing 10μmol/L curcumin). The effect of curcumin on expressions of combination of β-TrCP1 and Smad4 was examined by Co-Immunoprecipitation after human embryonic kidney cell line 293T were divided into 293T control group (no treatments were given), 293T curcumin group (treated with cell culture medium containing 10μmol/L curcumin) and 293T Jab1 group (trans?fected by HA-Jab1 plasmid). Results Compared with expressions in pericarcinomatous tissues, Smad4 was down regulated while the expression of Jab1 was upregulated in PC tissues (P<0.01), and the expression of Smad4 was negatively correlated with the expression of Jab1 (n=21, r=-0.71, P=0.007). After treated with curcumin, the protein expression of p53, Smad4 and p27 was increased in PANC1 cell, and the protein expression of the combination ofβ-TrCP1 and Smad4 was decreased in 293T cell (P<0.05). After transfected by HA-Jab1 plasmid, the protein expression of the combination ofβ-TrCP1 and Smad4 was increased in 293T cell (P<0.05). Conclusion Curcumin may have suppression effect of PC through increasing the protein expression of p53, Smad4 and p27, and the mechanism of Smad4 upregulation may be related with the inhibition of Smad4 ubiquitination process, while Jab1 may be also involved in Smad4 degradation through ubiquitination.

The Serotonin-6 Receptor as a Novel Therapeutic Target

Serotonin (5-hydroxytryptamine, 5-HT) is an important neurotransmitter that is found in both the central and peripheral nervous systems. 5-HT mediates its diverse physiological responses through 7 different 5-HT receptor families: 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT5, 5-HT6, and 5-HT7 receptors. Among them, the 5-HT6 receptor (5-HT6R) is the most recently cloned serotonin receptor and plays important roles in the central nervous system (CNS) and in the etiology of neurological diseases. Compared to other 5-HT receptors, the 5-HT6R has been considered as an attractive CNS therapeutic target because it is expressed exclusively in the CNS and has no known isoforms. This review evaluates in detail the role of the 5-HT6R in the physiology and pathophysiology of the CNS and the potential usefulness of 5-HT6R ligands in the development of therapeutic strategies for the treatment of CNS disorders. Preclinical studies provide support for the use of 5-HT6R ligands as promising medications to treat the cognitive dysfunction associated with Alzheimer's disease, obesity, depression, and anxiety.

Clinicopathological Significance of Expression of Tspan-1, Jab1 and p27 in Human Hepatocellular Carcinoma

The aim of this study was to investigate the expression of Tspan-1, Jab1 and p27 in human hepatocellular carcinoma (HCC) and their clinicopathological significance. The expression of Tspan-1, Jab1 and p27 was detected in HCC tissues, the tissues around cancer (76 cases), and the normal tissues around the liver hemangiomas (10 cases). The overexpression of Tspan-1 and Jab1 was found in HCC tissues, positively correlated with clinical stage and negatively correlated with survival rate. The expression of p27 was found inversely linked to which of Tspan-1 and Jab1. In conclusion, the expression of Tspan-1, Jab1 and p27 is significantly associated with development of HCC. Overexpression of Tspan-1 and Jab1 suggests poor prognosis but overexpression of p27 may expect good prognosis for patients with HCC.

Effect of ketamine on the expression of hepatic stress protein IFIT1 and JAB1 during the early stage of burns in mice / 重庆医科大学学报

Objective:To evaluate the effect of ketamine on the expression level of hepatic stress protein IFIT1 and JAB1 during the early stage of burns in mice, and observe the location of IFIT1 and JAB1 in hepatic cells. Methods:15 C57/129 male mice were divided randomly into three groups(n=5): normal control,burns,burns+ketamine. Burns group and burns+ketamine group were inflicted with 15%~20% TBSA full thickness burn injury,and burns+ketamine group received an intramuscular injection of 10 mg/kg ketamine 15 min after burns. At 4 h after burns,hepatic tissue was taken from mice,and the levels of hepatic I- FIT1 and JAB1 were detected by western blot. Normal control hepatic pathological section was taken; then cell location of I- FIT1 and JAB1 was detected by immunohistochemistry. Results:In burns group, the expression level of hepatic IFIT1 signifi- cantly increased,while that of JAB1 decreased as compared with normal control(P

Correlation between C-JUN activation domain binding protein 1 and P27~(kip1) in ovarian cancer cell HO-8910 / 基础医学与临床

Objective To investigate the expression and relationship of Jab1 and P27kip1 in ovarian cancer cell HO-8910. Methods Cells were treated with serum starvation and release.The expression and distribution of Jab1 and P27kip1 were detected by western blot and subcellular fractionation.HO-8910 cells were transfected in vitro with pcDNA3.1-MYC-Jab1.Western blot as well as subcellular fractionation was used to detect the expression and localization of P27kip1.Results The growth of HO-8910 cells was blocked by serum starvation.P27kip1 increased while Jab1 decreased.The reverse changes were found after serum release.P27kip1 and Jab1 could form compound in HO-8910 cells detected by immunoprecipitation.48h after transfected by pcDNA3.1-MYC-Jab1,the expression of P27kip1 decreased and the distribution of P27kip1 translocated from nucleus into cytoplasma in HO-8910.Conclusion Jab1 may control the location and expression of P27kip1 through integrating with P27kip1,and participate in regulating the growth of ovarian cancer cells through interfering with the function of P27kip1.

Expression of JAB1 and P27~(kip1) in liver tissue of patients with hepatocellular carcinoma and its clinical significance / 基础医学与临床

Objective To investigate the expression of C-JUN activation domain binding protein 1(JAB1)and its relationship with expression of P27 protein in human hepatocellular carcinoma(HCC),and to determine whether JAB1 is associated with clinicopathological parameters and prognosis of HCC.Methods Immunohistochemical analysis was performed to investigate the expression of JAB1 and P27 in 76 cases of HCC and adjacent nontumorous tissues.Fresh tumor tissues and their adjacent nontumorous tissues from 8 cases of HCC were collected for Western blot and immunoprecipitation assays.Results The expression of JAB1 in HCC was significantly higher than that in adjacent nontumorous tissues.In contrast,P27 level was higher in nontumorous liver tissues than that in HCC.JAB1 overexpression was correlated with histological differentiation,serum alpha-fetoprotein(AFP)level and metastasis(P