HNF1α and CDX2 transcriptional factors bind to cadherin-17 (CDH17) gene promoter and modulate its expression in hepatocellular carcinoma

Cadherin-17 (CDH17) belongs to the cell adhesion cadherin family with a prominent role in tumorigenesis. It is highly expressed in human hepatocellular carcinoma (HCC) and is proposed to be a biomarker and therapeutic molecule for liver malignancy. The present study aims to identify the transcription factors which interact and regulate CDH17 promoter activity that might contribute to the up-regulation of CDH17 gene in human HCC. A 1-kb upstream sequence of CDH17 gene was cloned and the promoter activity was studied by luciferase reporter assay. By bioinformatics analysis, deletion and mutation assays, and chromatin immunoprecipitation studies, we identified hepatic nuclear factor 1a (HNF1a) and caudal-related homeobox 2 (CDX2) binding sites at the proximal promoter region which modulate the CDH17 promoter activities in two HCC cell lines (Hep3B and MHCC97L). A consistent down-regulation of CDH17 and the two transcriptional activators (HNF1a and CDX2) expression was found in the liver of mouse during development, as well as in human liver cancer cells with less metastatic potential. Suppression of HNF1a and CDX2 expression by small interfering RNA (siRNA) significantly down-regulated expressions of CDH17 and its downstream target cyclin D1 and the viability of HCC cells in vitro. In summary, we identified the minimal promoter region of CDH17 that is regulated by HNF1a and CDX2 transcriptional factors. The present findings enhance our understanding on the regulatory mechanisms of CDH17 oncogene in HCC, and may shed new insights into targeting CDH17 expression as potential therapeutic intervention for cancer treatment. © 2010 Wiley-Liss, Inc.preprin

Assessing the joint effect of population stratification and sample selection in studies of gene-gene (environment) interactions

<p>Abstract</p> <p>Background</p> <p>It is well known that the presence of population stratification (PS) may cause the usual test in case-control studies to produce spurious gene-disease associations. However, the impact of the PS and sample selection (SS) is less known. In this paper, we provide a systematic study of the joint effect of PS and SS under a more general risk model containing genetic and environmental factors. We provide simulation results to show the magnitude of the bias and its impact on type I error rate of the usual chi-square test under a wide range of PS level and selection bias.</p> <p>Results</p> <p>The biases to the estimation of main and interaction effect are quantified and then their bounds derived. The estimated bounds can be used to compute conservative p-values for the association test. If the conservative p-value is smaller than the significance level, we can safely claim that the association test is significant regardless of the presence of PS or not, or if there is any selection bias. We also identify conditions for the null bias. The bias depends on the allele frequencies, exposure rates, gene-environment odds ratios and disease risks across subpopulations and the sampling of the cases and controls.</p> <p>Conclusion</p> <p>Our results show that the bias cannot be ignored even the case and control data were matched in ethnicity. A real example is given to illustrate application of the conservative p-value. These results are useful to the genetic association studies of main and interaction effects.</p

Glycodelin suppresses endometrial cell migration and invasion but stimulates spheroid attachment

Glycodelin contains four isoforms with diverse biological functions. Glycodelin-A is potentially a diagnostic marker for cancer patients and receptivity marker of the secretory endometrium. Yet, direct evidence for the role of glycodelin in the regulation of endometrial epithelial cell migration, invasion and attachment of trophoblastic spheroids (blastocyst surrogate) is lacking. In this study, the human glycodelin gene was stably transfected into human endometrial (HEC1-B) cells. Forced expression of glycodelin in HEC1-B cells did not affect cell proliferation, cell viability or cell-cycle progression, but significantly reduced migration and invasion of the stably transfected cells (both P < 0.05). The migration rate returned to normal levels when the glycodelin-forced-expressing HEC1-B cells were treated with glycodelin RNAi. Furthermore, forced expression of glycodelin in HEC1-B cells significantly increased the attachment of trophoblastic spheroids onto the endometrial epithelial cells (P < 0.05). In summary, glycodelin suppressed endometrial cell migration and invasion but enhanced spheroid attachment. © 2012, Reproductive Healthcare Ltd.postprin

Neuroprotection in steroid therapy: a rodent model

Key Messages 1. Chronic steroid therapy causes disturbance in cell proliferation of the hippocampus and the subventricular zone. This may be the underlying cause of altered memory and cognitive function. 2. Co-administration of paroxetine (a class of antidepressants) during steroid therapy could counteract the destruction. Modification of the current steroid therapy regimen may be required.published_or_final_versio

Urine 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG), a specific marker of oxidative stress, using direct, isocratic LC–MS/MS : method evaluation and application in study of biological variation in healthy adults

2009-2010 > Academic research: refereed > Publication in refereed journalAccepted ManuscriptPublishe

Neurogenic hypothesis and psychiatric disorders

published_or_final_versio

Voluntary wheel running reverses the decrease in subventricular zone neurogenesis caused by corticosterone

Adult neurogenesis within the dentate gyrus of the hippocampus can be increased by voluntary exercise but is suppressed under stress, such as with corticosterone (CORT). However, the effects of exercise and corticosterone on the cell proliferation of the other traditional neurogenic site, the subventricular zone (SVZ) have been reported with controversial results. In addition, the co-treatment effects of voluntary exercise and corticosterone have not been investigated. This study aims to determine whether corticosterone can suppress cell proliferation in the SVZ, and whether this can be reversed by voluntary exercise. In the present study, the effect of chronic (4 weeks) corticosterone treatment and wheel running simultaneously on the SVZ cell proliferation of adult Sprague-Dawley rats was examined. The results showed that cell proliferation indicated by bromodeoxyuridine (BrdU) was increased by voluntary wheel running whereas it was decreased by corticosterone treatment within the SVZ of the rats without running. For the rats with both corticosterone treatment and wheel running, it was found that the number of BrdU-labeled cells was approximately at the same level as the vehicle control group. Furthermore, these proliferating cells expressed doublecortin (DCX), a migrating neuroblast marker. Wheel running increased the percentage of BrdU-labeled cells expressing DCX in the SVZ whereas corticosterone treatment decreased this percentage. Thus, chronic injection of corticosterone can decrease the number of proliferating cells while wheel running can reverse the decrease in cell proliferation within the SVZ to normal levels. In addition, corticosterone can suppress the cell differentiation within the SVZ and this was alleviated by wheel running as indicated by the double-labeling of BrdU and DCX.published_or_final_versio

Disruption of the Vad1.3 gene causes defective spermatogenesis and loss of preimplantation embryo

Conference Theme: The Intersection Between Genetics, Genomics, and Reproductive BiologySubfertility affects 10-15 percent of couples worldwide, and male factor is one of the dominant causes accounted for one third of these cases. Notably 40-90 percent male subfertility is due to idiopathic defective sperm production. Today, hundreds of genes have been shown to be involved in the regulation of spermatogenesis. Previously, we identified from the rat testis a novel acrosome-specific gene Vad1.3 in a retinol-treated ...postprintThe 43rd Annual Meeting of the Society for the Study of Reproduction (SSR), Milwaukee, WI., 30 July-3 August 2010. In Biology of Reproduction, 2010, v. 83 Meeting abstracts, p. 88, abstract no. 39

Olfactomedin1 (Olfm1) in fallopian tube may modulate tubal ectopic pregnancy in humans: evidence from Immunohistochemistry and an in vitro coculture model

Conference Theme: The Intersection Between Genetics, Genomics, and Reproductive BiologyOlfactomedins are secretary glycoprotein constituted in the extracellular matrix (ECM) of various cell types. Recent studies suggested that Olfm-1 is down-regulated during the window of implantation (WOI) in the human endometrium and up-regulated in pathological condition like endometriosis and recurrent spontaneous abortions. Ectopic pregnancy is a gynaecological emergency and fertility threatening phenomenon which occurs in 1-2% of normal pregnancies and shows an increasing trend. Yet, tubal ectopic pregnancy accounts for more than 98% of the cases ...postprintThe 43rd Annual Meeting of the Society for the Study of Preproduction (SSR), Milwaukee, WI., 30 July-3 August 2010. In Biology of Reproduction, 2010, v. 83 n. Meeting abstracts, p. 27-28, abstract no. 13

Glycodelin-A primes zona pellucida-induced acrosome reaction of human spermatozoa via downregulation of extracellular signal regulated kinases and enhancement of zona pellucida-induced calcium influx

Conference Theme: The Intersection Between Genetics, Genomics, and Reproductive BiologypostprintThe 43rd Annual Meeting of the Society for the Study of Reproduction (SSR), Milwaukee, WI., 30 July-3 August 2010. In Meeting Abstracts, 2010, p. 38, abstract no. 17