Androgen Receptor Stimulates Hexokinase 2 and Induces Glycolysis by PKA/CREB Signaling in Hepatocellular Carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) escapes growth inhibition by upregulating hexokinase 2 (HK2); however, the mechanism by which tumor cells upregulate HK2 remains unclear. AIM: We aimed to investigate the role of androgen receptor (AR) signalling in promoting HK2 expression in HCC. METHODS: The expressions of AR and HK2 in HCC tissues were analyzed by immunohistochemistry. Cell proliferation was determined using the CCK-8 assay, and the molecular mechanism of AR in the regulation of HK2 was evaluated by immunoblotting and luciferase assays. RESULTS: AR expression is positively correlated with HK2 staining by an immunohistochemical analysis. The manipulation of AR expression changed HK2 expression and glycolysis. AR signaling promoted the growth of HCC by enhancing HK2-mediated glycolysis. Moreover, AR stimulated HK2 levels and glycolysis by potentiating protein kinase A/cyclic adenosine monophosphate response element-binding (CREB) protein signaling. CREB silencing decreased HK2 expression and inhibited AR-mediated HCC glycolysis. AR affected the sensitivity of HCC cells to glycolysis inhibitors by regulating downstream phosphorylated (p)-CREB. CONCLUSIONS: These results indicate that AR at least partially induced glycolysis via p-CREB regulation of HK2 in HCC cells. Thus, this pathway should be considered for the design of novel therapeutic methods to target AR-overexpressing HCC.

[Expression of proBNP and NT-proBNP in Sudden Death of Coronary Heart Disease].

OBJECTIVES: To study the expression change of pro-brain natriuretic peptide （proBNP） and N-terminal pro-brain natriuretic peptide （NT-proBNP） in sudden death of coronary atherosclerotic heart disease, and to explore its application in forensic diagnosis. METHODS: Myocardial and blood samples were collected from normal control group, sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group （20 cases in each group）. The expression of proBNP in myocardial samples were detected by immunohistochemical staining and Western blotting, and that of BNP mRNA were detected by reverse transcription PCR （RT-PCR）. The content of NT-proBNP in plasma were detected by ELISA. RESULTS: Immunohistochemical staining showed positive expression of proBNP in both sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group. There was no positive expression in normal control group. For sudden death of coronary atherosclerotic heart disease group and single coronary stenosis group, the relative expression of proBNP protein and BNP mRNA in myocardial tissue and the NT-proBNP content in plasma were higher than that of normal control group （P<0.05）. The NT-proBNP content in plasma of sudden death of coronary atherosclerotic heart disease group was higher than that of single coronary stenosis group （P<0.05）. CONCLUSIONS: In myocardial ischemia condition, the higher expression of proBNP in cardiac muscle cell shows that the detection of NT-proBNP in plasma can be useful to differentially diagnose the degree of coronary atherosclerotic heart disease and determine whether the sudden death due to coronary atherosclerotic heart disease.

A comprehensive review of microRNA-related polymorphisms in gastric cancer.

MicroRNAs (miRNAs) are a class of small non-coding RNA molecules of about 22 nucleotides in length. miRNAs are highly conserved in both plants and animals, and function as gene regulators by binding to the 3'-untranslated region of target mRNAs for cleavage and/or translational repression. miRNA biogenesis, stability, and regulation of expression are strongly sequence dependent. Sequence variants, such as single nucleotide polymorphisms (SNPs) in pri-miRNA, pre-miRNA, promoter regions, or miRNA-target sites, can influence miRNA function, thereby contributing to the pathological features of human disease. In this review, we focus on miRNA-related SNPs in gastric cancer and comprehensively analyze some commonly studied SNPs.

A study on the relationship between TCTA tetranucleotide polymorphism of the HPRT gene and primary hyperuricemia.

We examined polymorphism of the TCTA tetranucleotide sequence in the 3rd intron of the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene in the Han population of Ningxia Province in China. We also looked for a possible relationship between STR polymorphism in the 3rd intron of the HPRT gene and primary hyperuricemia. We used Chelex-100 to extract DNA, then PCR, PAGE and silver staining for allele genotyping and DNA sequencing to obtain the distribution of the alleles. We found, for the first time, that there is high STR polymorphism in the 3rd intron of the HPRT gene. We detected 5 STR alleles in this intron in the Han population of Ningxia Province, with 15 genotypes in females; significant differences were observed in the distribution of alleles and genotypes between control and patient groups for both males and females. Alleles of the TCTA repeat in the 3rd intron of the HPRT gene were found to be associated with primary hyperuricemia; consequently, these alleles may be considered risk factors for primary hyperuricemia.

A new single-nucleotide mutation (rs362719) of the reelin (RELN) gene associated with schizophrenia in female Chinese Han.

Reelin is an extracellular signaling protein that plays an important role in the development of the central nervous system. Post-mortem studies have shown lower reelin protein levels in the brains of patients with schizophrenia and bipolar disorder compared with controls. Genetic studies have also shown that mutations in the reelin gene (RELN) increase the risk for schizophrenia and bipolar disorder. We evaluated whether an RELN gene variant, rs362719, which has been associated with increased susceptibility to bipolar disorder, is also associated with susceptibility to schizophrenia. We included 405 Chinese Han schizophrenia patients and 390 controls in our study. The polymorphism was genotyped by PCR and RFLP methods. We found a significant difference in allele frequency distribution (P< 0.05) between schizophrenia patients and controls. The frequency of the A allele was significantly higher in schizophrenia patients than in healthy controls. The effect of SNP rs362719 on allele distribution was significant in female (P < 0.05) but not in male participants (P = 0.473). Besides the gender factor, demographic and clinical characteristics of the rs362719 genotype groups were also analyzed using the chi-square test, but no significant differences were found. We conclude that rs362719 of the RELN gene is associated with susceptibility to schizophrenia in Chinese Han, possibly through a gender-specific mechanism. Further studies will be needed to confirm this genetic risk factor for schizophrenia.

Polymorphisms of three new microsatellite sites of the dystrophin gene.

To look for novel microsatellites in the dystrophin gene for the diagnosis of Duchenne muscular dystrophy, candidate microsatellite sites in the dystrophin gene were analyzed with the SSRHunter software and were also genotyped. Among the 15 candidate microsatellite sites, three novel microsatellite sites in the 60th, 30th, and 2nd intron were found to have a high degree of polymorphism. We submitted these three new loci to the European Molecular Biology Laboratory, under accession Nos. FN547040, FN547041 and FN557526, which were called DXSDMD-in60, DXSDMD-in30 and DXSDMD-in2, respectively. In these three loci, we found 9, 6 and 11 alleles, respectively, in the 205 individuals. In addition, we also detected 20, 19 and 20 genotypes for the three loci in female samples, with a polymorphism information content of more than 0.600. In conclusion, the three microsatellite sites in the intron region of the dystrophin gene have a high degree of polymorphism, and they can be used in population genetics, as well as to provide a theoretical basis for genetic diagnosis and elucidation of molecular mechanisms in Duchenne muscular dystrophy.

The G-712A polymorphism of brain-derived neurotrophic factor is associated with major depression but not schizophrenia.

Brain-derived neurotrophic factor (BDNF) is needed to support neuronal survival and differentiation. It also promotes synaptic remodeling and modulates the function of many other neurotransmitters. BDNF is implicated in major depression (MD), and to a lesser extent, in schizophrenia. In the current study, we examined BDNF polymorphisms (G-712A, C270T and Val66Met) in 202 patients with MD and 323 patients with schizophrenia. Results were compared to 346 healthy individuals. The analysis revealed a strong association between the G-712A genotype distribution and MD (p=0.0005). The frequency of the -712A allele was significantly higher in MD patients than in the healthy controls (p=0.0007). The -712AG heterozygote was associated with higher Hamilton score in MD patients. No association was found between schizophrenia and the three BDNF variants. These findings support an important role of G-712A polymorphism of BDNF in MD, and may guide future studies to identify genetic risk factors for MD.

Association study of polymorphisms in the promoter region of DRD4 with schizophrenia, depression, and heroin addiction.

This study investigated the possible association between three functional polymorphisms in the promoter region of the dopamine D4 receptor (DRD4) gene and schizophrenia, depression, and heroin addiction. Genomic DNA was isolated from the venous blood leukocytes of 322 unrelated patients with schizophrenia, 156 patients with depression, 300 patients with heroin addiction, and 300 healthy unrelated individuals. Polymorphisms in the promoter region of DRD4 (-120 bp duplication, -616C/G, and -521C/T) were genotyped using allele-specific polymerase chain reaction analysis. Genotype and allele were analyzed using SPSS 11.5 software. Results of this analysis indicated that there is a strong finding of -120 bp duplication allele frequencies with schizophrenia (p=0.008) and weak finding with -1240 L/S and for paranoid schizophrenia (p=0.022). Interestingly, there is a stronger finding with -521 C/T allele frequencies with heroin dependence (p=0.0002). These observations strongly suggest that the -120-bp duplication polymorphism of DRD4 is associated with schizophrenia and that the -521 C/T polymorphism is associated with heroin addiction.