Histochemical and immunohistochemical investigation of guanase and nedasin in human tissues

Kubo, Ken Ichiro; Honda, Hirohito; Sannomiya, Katsutaka; Aying, Yuan; Mao, Wei; Shen, Mi; Aoyagi, Eriko; Simizu, Ichiro; Ii, Kunio; Ito, Susumu

doi:10.2152/jmi.53.264

Cited by 6 publications

(5 citation statements)

References 14 publications

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“…Quantitative PCR analysis of heterogeneous tumor tissues cannot distinguish between expression levels in specific cellular phenotypes which might limit the discriminatory power of this method. Nevertheless, our observation of BAAT40 and GAD41, two enzymes involved in bile acid and purine metabolism in the adult liver, being weaker expressed in immature embryonal HB as compared to predominantly fetal tumors may suggest that high miR‐492 expression might be associated with the immature and advanced C2 type of HB. Interestingly, we detected a correlation of miR‐492 and KRT19 with the lack of β‐catenin mutation, a clinicopathological characteristic which was not associated with a distinct subgroup by the Cairo et al study 18.…”

Section: Discussionmentioning

confidence: 85%

MicroRNA-492 is processed from the keratin 19 gene and up-regulated in metastatic hepatoblastoma

et al. 2011

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MicroRNAs (miRNAs) are well-known regulators of proliferation, apoptosis, and differentiation and are recognized to play an important role in the development of cancers. Here we aimed to identify the functional contribution of miRNAs to the biology of hepatoblastoma (HB), the most common malignant liver tumor in childhood. As overexpression of the oncogene PLAG1 (pleomorphic adenoma gene 1) is a characteristic phenomenon in HB, we used RNA interference and subsequent miRNA array analysis to identify miR-492 as most strongly influenced by PLAG1. We provide novel experimental evidence that miR-492 can originate from the coding sequence of the HB marker gene keratin 19 (KRT19). In agreement with these in vitro observations, significantly elevated levels of coexpressed KRT19 and miR-492 were particularly found in metastatic HB tumor samples. Stable overexpression of miR-492 in HB cell clones served to identify a broad range of differentially expressed transcripts, including several candidate targets of miR-492 predicted by computational algorithms. Among those the liver enzyme BAAT showed significant association with miR-492 expression in HB tumor samples. Conclusion: A close functional relationship between KRT19 and miR-492 was identified that may play an important role in the progression of malignant embryonal liver tumors. Additionally, miR-492 and its associated targets might serve as new HB biomarkers of clinical utility and could assist to explore targeted therapies, especially in metastatic HB with a poor prognosis. (HEPATOLOGY 2011;53:833-842) H epatoblastoma (HB) is the most common primary liver neoplasia in childhood.1 This highly malignant tumor derives from undifferentiated hepatic progenitor cells, which undergo malignant transformation during embryogenesis. 2With preoperative and postoperative chemotherapy, achievement of complete resection, event-free survival (EFS), and overall survival (OS) among children with standard-risk HB is quite excellent (3-year EFS and OS about 90%3 ). However, in high-risk HB patients with metastatic disease and low a-fetoprotein (AFP) levels, EFS and OS remains poor irrespective of the chemotherapy used (3-year EFS and OS about 50% 4,5 ). On the molecular level, mutations in the bcatenin gene leading to constitutive activation of the Wnt/b-catenin pathway have been detected in a large proportion of HB. 6,7 Moreover, activation of the insulin-like growth factor (IGF) axis 8-10 as well as amplification of the chromosomal region (8q11.2-q13) and up-regulation of the therein located transcription factor PLAG1 (pleomorphic adenoma gene 1) have been frequently found in HB.10 Overexpression of the oncogene PLAG1 is a characteristic phenomenon not only for HB but for several types of cancers.11 Ectopic PLAG1 expression has been demonstrated to induce uncontrolled cell proliferation. 12,13 Physiologically, PLAG1 is a transcription factor expressed during fetal development 14 and is known to activate several target

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Section: Discussionmentioning

confidence: 85%

MicroRNA-492 is processed from the keratin 19 gene and up-regulated in metastatic hepatoblastoma

et al. 2011

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“…The enzyme is highly expressed in liver, brain, kidney and placenta [26], [27]. Furthermore, GDA is also involved in the regulation of dendrite development as a positive regulator by modulating guanine concentrations [26].…”

Section: Resultsmentioning

confidence: 99%

Pan-Pathway Based Interaction Profiling of FDA-Approved Nucleoside and Nucleobase Analogs with Enzymes of the Human Nucleotide Metabolism

et al. 2012

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To identify interactions a nucleoside analog library (NAL) consisting of 45 FDA-approved nucleoside analogs was screened against 23 enzymes of the human nucleotide metabolism using a thermal shift assay. The method was validated with deoxycytidine kinase; eight interactions known from the literature were detected and five additional interactions were revealed after the addition of ATP, the second substrate. The NAL screening gave relatively few significant hits, supporting a low rate of “off target effects.” However, unexpected ligands were identified for two catabolic enzymes guanine deaminase (GDA) and uridine phosphorylase 1 (UPP1). An acyclic guanosine prodrug analog, valaciclovir, was shown to stabilize GDA to the same degree as the natural substrate, guanine, with a ΔTagg around 7°C. Aciclovir, penciclovir, ganciclovir, thioguanine and mercaptopurine were also identified as ligands for GDA. The crystal structure of GDA with valaciclovir bound in the active site was determined, revealing the binding of the long unbranched chain of valaciclovir in the active site of the enzyme. Several ligands were identified for UPP1: vidarabine, an antiviral nucleoside analog, as well as trifluridine, idoxuridine, floxuridine, zidovudine, telbivudine, fluorouracil and thioguanine caused concentration-dependent stabilization of UPP1. A kinetic study of UPP1 with vidarabine revealed that vidarabine was a mixed-type competitive inhibitor with the natural substrate uridine. The unexpected ligands identified for UPP1 and GDA imply further metabolic consequences for these nucleoside analogs, which could also serve as a starting point for future drug design.

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“…GDA is a functional candidate based on its function as a regulator of dendrite patterning and synaptic formation between hippocampal neurons 25,26 and its involvement in dopamine and glutamate signaling. [27][28][29] Tannu et al 29 showed significant decrease in GDA in Rhesus monkeys following cocaine self-administration.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project

Perroud

Uher

et al. 2010

Pharmacogenomics J

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Suicidal thoughts during antidepressant treatment have been the focus of several candidate gene association studies. The aim of the present genome-wide association study was to identify additional genetic variants involved in increasing suicidal ideation during escitalopram and nortriptyline treatment. A total of 706 adult participants of European ancestry, treated for major depression with escitalopram or nortriptyline over 12 weeks in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study were genotyped with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). A total of 244 subjects experienced an increase in suicidal ideation during follow-up. The genetic marker most significantly associated with increasing suicidality (8.28 × 10(-7)) was a single-nucleotide polymorphism (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase (GDA) on chromosome 9q21.13. Two suggestive drug-specific associations within KCNIP4 (Kv channel-interacting protein 4; chromosome 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome 8p21.1) were found in subjects treated with escitalopram. Suggestive drug by gene interactions for two SNPs near structural variants on chromosome 4q12, one SNP in the apolipoprotein O (APOO) gene on chromosome Xp22.11 and one on chromosome 11q24.3 were found. The most significant association within a set of 33 candidate genes was in the neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene. Finally, we also found trend for an association within genes previously associated with psychiatric phenotypes indirectly linked to suicidal behavior, that is, GRIP1, NXPH1 and ANK3. The results suggest novel pathways involved in increasing suicidal ideation during antidepressant treatment and should help to target treatment to reduce the risk of this dramatic adverse event. Limited power precludes definitive conclusions and replication in larger sample is warranted.

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Histochemical and immunohistochemical investigation of guanase and nedasin in human tissues

Cited by 6 publications

References 14 publications

MicroRNA-492 is processed from the keratin 19 gene and up-regulated in metastatic hepatoblastoma

MicroRNA-492 is processed from the keratin 19 gene and up-regulated in metastatic hepatoblastoma

Pan-Pathway Based Interaction Profiling of FDA-Approved Nucleoside and Nucleobase Analogs with Enzymes of the Human Nucleotide Metabolism

Genome-wide association study of increasing suicidal ideation during antidepressant treatment in the GENDEP project

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