Relationship of Ornithine Decarboxylase activity and histological findings in human hepatocellular carcinoma

Tamori, Akihiro; Nishiguchi, S; Kuroki, Tetsuo; Seki, Shuichi; Kobayashi, Kenzo; Kinoshita, Hiroaki; Otani, Shuzo

doi:10.1002/hep.1840200512

Cited by 27 publications

(17 citation statements)

References 19 publications

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“…The overexpression of ODC in transgenic mice has resulted in phenotypic alterations in the skin leading to tumorigenesis (Megosh et al, 1995). Elevated ODC activity has been reported in several human cancers, including breast (Romano et al, 1986); stomach (Lundell and Rosengren, 1986), colon (Radford et al, 1990) and liver (Tamori et al, 1994). Restoration of ODC-Az function in hepatocellular carcinoma cell lines results in reduction of ODC activity and slower proliferation rates.…”

Section: Discussionmentioning

confidence: 99%

Reduction of ornithine decarboxylase antizyme (ODC-Az) level in the 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model

et al. 1998

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Ornithine decarboxylase (ODC) activity is elevated in and necessary for oral carcinogenesis, but the mechanism for its deregulation is unclear. Using subtractive hybridization, a 1029 bp full-length cDNA encoding a 222 amino acid open reading frame has been isolated from normal hamster oral keratinocytes. The hamster cDNA is homologous to the human, mouse and rat ornithine decarboxylase antizyme gene (ODC-Az). The hamster ODC-Az gene demonstrated a restriction fragment length polymorphism (RFLP) upon Southern blot analysis comparing normal and tumor hamster genomic DNA. Northern blot analysis revealed that normal hamster oral keratinocytes express readily detectable level of ODC-Az mRNA. Malignant oral keratinocytes demonstrate reduced expression of the ODC-Az mRNA. In contrast, malignant hamster oral keratinocytes have elevated ODC mRNA levels and lengthened ODC protein halflife when compared to the normal counterparts. This was corroborated by direct measurement of ODC enzymatic activity. These data support the hypothesis that the reduced and/or loss of expression and function of the ODC-Az gene is an important event for the early de-regulation of cellular proliferation during oral tumor development.

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Section: Discussionmentioning

confidence: 99%

Reduction of ornithine decarboxylase antizyme (ODC-Az) level in the 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model

et al. 1998

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“…Ectopic overexpression of ODC in vivo (transgenic mice) and in vitro results in tumor formation and transformation (Cliord et al, 1995;Megosh et al, 1995). Elevated levels of ODC activity have been reported in several cancers including breast (Romano et al, 1986), stomach (Lundell and Rosengren, 1986), colon (Radford et al, 1990) and liver (Tamori et al, 1994).…”

Section: Introductionmentioning

confidence: 99%

Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by ornithine decarboxylase antizyme

et al. 2001

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The hamster ornithine decarboxylase antizyme (ODCAz) cDNA was transfected into the hamster malignant oral keratinocyte cell line, HCPC-1. Ectopic expression of ODC-Az resulted in the reversion of malignant phenotypes and alteration of DNA methylation status of CCGG sites. The phenotypes examined include ODC enzymatic activity, doubling time, morphological change, anchorage dependent growth, tumorigenicity in nude mice, induction of epithelial dierentiation marker protein (involucrin), and change of cell cycle position. Comparison of CCGG DNA methylation status of the ODC-Az and control vector transfectants revealed a signi®cant increase in demethylation of 5-methyl cytosines (m 5 C) of CCGG sites in the ODC-Az transfectants. Ectopic expression of ODC-Az gene in hamster malignant oral keratinocytes led to reduce ODC activity and the subsequent demethylation of 5-methyl cytosines, presumably via the ODC/ polyamines/ decarboxylated S-adenosylmethionine (dc-AdoMet) pathways. Our data suggest that ODC-Az shared the same pathway of polyamines/ dc-AdoMet/DNA methyltransferase (DNA MTase). We propose that ODC-Az mediates a novel mechanism in tumor suppression by DNA demethylation and presumably re-activation of key cellular genes silenced by DNA hypermethylation during cancer development. Oncogene (2001) 20, 24 ± 33.

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“…Deregulated polyamine biosynthesis as indicated by overexpressed ornithine decarboxylase (ODC) 1 activity is a well recognized characteristic of animal and human cancers. In at least one tumor type, the genetic basis for this has been attributed to a point mutation leading to stabilization of the enzyme protein (1).…”

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confidence: 99%

Correlation of Polyamine and Growth Responses to N 1,N 11-Diethylnorspermine in Primary Fetal Fibroblasts Derived from Transgenic Mice Overexpressing Spermidine/SpermineN 1-Acetyltransferase

Alhonen¹,

Karppinen²,

Uusi‐Oukari³

et al. 1998

Journal of Biological Chemistry

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A recently generated transgenic mouse line having activated polyamine catabolism due to systemic overexpression of spermidine/spermine N 1 -acetyltransferase (SSAT) was used to isolate primary fetal fibroblasts as a means to further elucidate the cellular consequences of activated polyamine catabolism. Basal levels of SSAT activity and steady-state mRNA in the transgenic fibroblasts were about ϳ20-and ϳ40-fold higher than in nontransgenic fibroblasts. Consistent with activated polyamine catabolism, there was an overaccumulation of putrescine and N 1 -acetylspermidine and a decrease in spermidine and spermine pools. Treatment with the polyamine analogue N 1 ,N 11 -diethylnorspermine (DENSPM) increased SSAT activity in the transgenic fibroblasts ϳ380-fold, whereas mRNA increased only ϳ3-fold, indicating post-mRNA regulation. SSAT activity in the nontransgenic fibroblasts increased ϳ200-fold. By Western blot, enzyme protein was found to increase ϳ46 times higher in the treated transgenic fibroblasts than non-transgenic fibroblasts: a value comparable to 36-fold differential in enzyme activity. With DENSPM treatment, spermidine pools were more rapidly depleted in the transgenic fibroblasts than in nontransgenic fibroblasts. Similarly, transgenic fibroblasts were much more sensitive to DENSPM-induced growth inhibition. This was not diminished by co-treatment with an inhibitor of polyamine oxidase, suggesting that growth inhibition was due to polyamine depletion per se as opposed to oxidative stress. Since the two fibroblasts were genetically identical except for the transgene, the various metabolic and growth response differences are directly attributable to overexpression of SSAT.Deregulated polyamine biosynthesis as indicated by overexpressed ornithine decarboxylase (ODC) 1 activity is a well recognized characteristic of animal and human cancers. In at least one tumor type, the genetic basis for this has been attributed to a point mutation leading to stabilization of the enzyme protein (1). Although several groups have reported that ODC may play a causative role in the process of cell transformation in cultured systems (2)(3)(4), that function appears to be attenuated in vivo. Transgenic mice that systemically overexpress native ODC by at least 20-fold fail to show an increased incidence of tumors in any of their tissues (5). More likely, the enzyme interacts with other genes to fulfill a facilitating role in tumorigenesis not unlike that seen with oncogene cooperativity, a phenomenon that has been previously demonstrated between ODC and ras (6). This potential is clearly indicated in mouse skin carcinogenesis models where induction of ODC activity represents an early response to tumor promoters (7) and is known to be critical to tumor formation (8, 9). In this regard, O'Brien's group (10) recently reported that transgenic mice that overexpress a stabilized form of ODC in the skin are much more susceptible to 7,12-dimethylbenz(a)anthracene-induced carcinogenesis. In addition, their findings strongly suggest that am...

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Relationship of Ornithine Decarboxylase activity and histological findings in human hepatocellular carcinoma

Cited by 27 publications

References 19 publications

Reduction of ornithine decarboxylase antizyme (ODC-Az) level in the 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model

Reduction of ornithine decarboxylase antizyme (ODC-Az) level in the 7,12-dimethylbenz(a)anthracene-induced hamster buccal pouch carcinogenesis model

Induction of epithelial differentiation and DNA demethylation in hamster malignant oral keratinocyte by ornithine decarboxylase antizyme

Correlation of Polyamine and Growth Responses to N 1,N 11-Diethylnorspermine in Primary Fetal Fibroblasts Derived from Transgenic Mice Overexpressing Spermidine/SpermineN 1-Acetyltransferase

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