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A Horii

Publications and source records attributed to A Horii.

At least 19 recordsLinked to original sources
PubMed2001

Frequent nuclear accumulation of beta-catenin in pituitary adenoma.

BACKGROUND: Beta-catenin (CTNNB1) is known to be a member of the cadherin-catenin superfamily and to function in cell-cell adhesion. However, it also has been reported that CTNNB1 plays an important role in carcinogenesis. In the current study, the authors observed expression of the CTNNB1 protein in primary pituitary adenomas to investigate the role of CTNNB1 in the development of pituitary adenomas. METHODS: A total of 37 pituitary adenomas were analyzed. Expression of CTNNB1 and the cell proliferation marker Ki-67 were observed immunohistochemically. In addition, the authors performed direct sequencing to detect somatic mutations of exon 3 of the CTNNB1 gene. RESULTS: Twenty-one of 37 pituitary adenomas (57%) demonstrated abnormal nuclear accumulation of CTNNB1. It is interesting to note that tumors with an accumulation of CTNNB1 in the nucleus showed a statistical tendency toward an association with increased immunoreactivity of Ki-67 (P < 0.05) whereas no significant correlation was detected between the status of CTNNB1 and other clinicopathologic features. Missense mutations in exon 3 of the CTNNB1 gene also were detected in the cases with abnormal nuclear accumulation of the CTNNB1 protein. CONCLUSIONS: The results of the current study suggest that up-regulation of the Wnt signaling pathway, including accumulation of mutant CTNNB1 in the nuclei, plays an important role in the tumorigenesis and development of adenoma in the pituitary gland.

Adenoma↗
PubMed2001

RIZ, the retinoblastoma protein interacting zinc finger gene, is mutated in genetically unstable cancers of the pancreas, stomach, and colorectum.

The retinoblastoma protein interacting zinc finger (RIZ) gene is a candidate tumor suppressor gene on 1p36, a region frequently rearranged in a wide variety of human tumors. As the RIZ gene harbors several microsatellites within its coding region, it is a candidate for an inactivating mutation in microsatellite instability (MSI) mediated carcinogenesis. In this study, we examined mutations of two poly adenine tracts, A(8) and A(9), within the coding region of the RIZ gene, in MSI-high (MSI-H) primary cancers occurring in the pancreas, stomach, and colorectum. Frameshift mutations were found in one (10%) of 10 pancreatic, four (36%) of 11 gastric, and two (25%) of eight colorectal cancers. These results indicate that mutations of the RIZ gene play an important role in the pathogenesis of some MSI-H cancers.

Colorectal Neoplasms↗
PubMed2000

Molecular cloning and expression of cDNA encoding chicken UDP-N-acetyl-D-glucosamine (GlcNAc): GlcNAcbeta 1-6(GlcNAcbeta 1-2)- manalpha 1-R[GlcNAc to man]beta 1,4N-acetylglucosaminyltransferase VI.

A cDNA that encodes UDP-N-acetyl-d-glucosamine (GlcNAc):GlcNAcbeta1-6(GlcNAcbeta1-2)Manalpha1-R[GlcNA c to Man]beta1, 4N-acetylglucosaminyltransferase VI (GnT VI), which is responsible for the formation of pentaantennary asparagine-linked oligosaccharides (N-glycans), has been cloned from a hen oviduct cDNA library based on the partial amino acid sequences of the purified enzyme. The isolated cDNA clone contained an open reading frame encoding 464 amino acids, including all of the peptides that were sequenced. The deduced amino acid sequence predicts a type II transmembrane topology and contains two potential N-glycosylation sites. The primary structure was found to be significantly similar to human GnT IV-homologue, the gene for which was cloned from the deleted region in pancreatic cancer, and to human and bovine GnT IVs. Chicken GnT VI-transfected COS-1 cells showed a high GnT VI activity (26.8 pmol/h/mg protein), whereas nontransfected, mock-transfected, or human GnT IV-homologue-transfected COS-1 cells had no activity. Northern blot analysis using poly(A)(+) RNA from hen oviduct indicated that the size of GnT VI mRNA is 2.1 kilobases. Reverse transcription-polymerase chain reaction analysis showed that GnT VI mRNA was relatively highly expressed in oviduct, spleen, lung, and colon.

Amino Acid Sequence↗
PubMed2000

Degree of apoptosis induced by adenovirus-mediated transduction of p53 or p73alpha depends on the p53 status of glioma cells.

It has been reported that U-87MG glioma cells with wild-type p53 are resistant to p53 replacement gene therapy. As some gliomas harbor wild-type p53, it would be important to override the resistance mechanism due to wild-type p53 in glioma gene therapy. In this study, we transduced U-87MG cells or U251 glioma cells harboring mutated p53 with the p53 or p73alpha gene (a homologue of p53, that differently induces some p53-responsive genes) via adenovirus vectors (Advs) at same multiplicities of infection (MOIs) into respective cells (U-87MG: MOI 1000, U251: MOI 100), and evaluated the degree of apoptosis. The results demonstrate that the degree of apoptosis induced by Adv-mediated transduction of p53 in U-87MG cells was lower than that in U251 cells, whereas that induced by Adv-mediated transduction of p73alpha in U-87MG cells was higher than that in U251 cells. Bax expression in U-87MG and U251 cells induced by Adv-mediated transduction of p53 was almost the same as that of p73alpha. On the other hand, Adv-mediated transduction of p73alpha induced caspase-9 at higher levels than that of p53 in both cells. The results indicate that Adv-mediated transduction of p73alpha might be beneficial to overcome the resistance mechanism of glioma cells harboring wild-type p53.

Adenoviridae↗
PubMed2000

Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability.

Many lines of evidence suggest that the retinoblastoma protein interacting zinc finger gene RIZ is a strong candidate for the tumor suppressor locus on 1p36, a region commonly deleted in many human cancers with chromosomal instability. In addition, a role for RIZ in tumors of the microsatellite instability pathway is suggested by frequent frameshift mutations in hereditary non-polyposis colorectal carcinomas. Here we studied RIZ mutations in sporadic cancers with microsatellite instability. Frameshift mutations in the two coding polyadenosine tracks of RIZ were found in 19 (48%) of 40 gastric carcinomas, 6 (33%) of 18 endometrial carcinomas, 14 (26%) of 51 of colorectal carcinomas, and 7 (54%) of 13 cell lines. Eleven tumor tissues showed biallelic inactivation of RIZ. In contrast, no frameshift mutations were found in 70 microsatellite stable tumors. These results suggest an important role for RIZ in sporadic cancers with microsatellite instability.

Alleles↗
PubMed2000

Identification and characterization of a 500-kb homozygously deleted region at 1p36.2-p36.3 in a neuroblastoma cell line.

Loss of heterozygosity of the distal region of chromosome 1p where tumor suppressor gene(s) might harbor is frequently observed in many human cancers including neuroblastoma (NBL) with MYCN amplification and poor prognosis. We have identified for the first time a homozygously deleted region at the marker D1S244 within the smallest region of overlap at 1p36.2-p36.3 in two NBL cell lines, NB-1 and NB-C201 (MASS-NB-SCH1), although our genotyping has suggested the possibility that both lines are derived from the same origin. The 800-kb PAC contig covering the entire region of homozygous deletion was made and partially sequenced (about 60%). The estimated length of the deleted region was 500 kb. We have, thus far, identified six genes within the region which include three known genes (DFF45, PGD, and CORT) as well as three other genes which have been reported during processing our present project for the last 3(1/2) years (HDNB1/UFD2, KIAA0591F/KIF1B-beta, and PEX14). They include the genes related to apoptosis, glucose metabolism, ubiquitin-proteasome pathway, a neuronal microtubule-associated motor molecule and biogenesis of peroxisome. At least three genes (HDNB1/UFD2, KIAA0591F/KIF1B-beta, and PEX14) were differentially expressed at high levels in favorable and at low levels in unfavorable subsets of primary neuroblastoma. Since the 1p distal region is reported to be imprinted, those differentially expressed genes could be the new members of the candidate NBL suppressor, although RT-PCR-SSCP analysis has demonstrated infrequent mutation of the genes so far identified. Full-sequencing and gene prediction for the region of homozygous deletion would elucidate more detailed structure of this region and might lead to discovery of additional candidate genes. Oncogene (2000) 19, 4302 - 4307

Carrier Proteins↗
PubMed2000

Identification of the homozygously deleted region at chromosome 1p36.2 in human neuroblastoma.

BACKGROUND: We have identified for the first time a homozygously deleted region within the smallest region of overlap at 1p36.2-3 in two neuroblastoma cell lines. PROCEDURE: The 800-kb PAC contig covering the entire homozygously deleted region was made and sequenced. To date, approximately 70% of sequencing has been accomplished, and the estimated length of the deleted region was 500 kb. RESULTS: Currently, we have found six genes within the region, which include three known genes as well as three other genes that have been reported during processing of our present project for the last 3(1/2) years. We report here the results of expression and mutation analyses of those genes. CONCLUSIONS: Full sequencing for the region of homozygous deletion as well as further analyses of the genes mapped within the region may reveal whether or not there is a neuroblastoma suppressor gene as proposed by the Knudson's two-hit hypothesis.

Child, Preschool↗
PubMed2000

Deletion mapping of 14q32 in human neuroblastoma defines an 1,100-kb region of common allelic loss.

BACKGROUND: We analyzed loss of heterozygosity (LOH) in 54 primary neuroblastomas (NBs) using 12 microsatellite markers on 14q32, and found that 31% (17/54) NBs showed LOH. PROCEDURE: The smallest region of overlap (SRO) was identified between D14S62 and D14S987. RESULTS: There was no statistical correlation between LOH and any clinicopathologic features, including age, stage, amplification of MYCN, and ploidy. A sequence-ready bacterial artificial chromosome (BAC) contig was constructed, and the minimum tiling path of six BACs covered the SRO; the physical length of this region was no larger than 1,000 kb. CONCLUSIONS: Our findings support the existence of a putative tumor-related gene on 14q32 for the tumorigenesis of NB.

Alleles↗
PubMed2000

p24/ING1-ALT1 and p47/ING1-ALT2, distinct alternative transcripts of p33/ING1.

p33/ING1s (the growth inhibitor ING1 and candidate tumor suppressor ING1) are key players in the suppressive pathways for human tumorigenesis. We analyzed their complete transcripts, primary structures, and expression. The results led us to discover two novel and related alternatively spliced transcripts encoding p24/ING1-ALT1 and p47/ING1-ALT2. They share C-terminal residues with the candidate tumor suppressors p33/ING1. The candidate tumor suppressors p33/ING1 and p24/ING1-ALT1 were coexpressed in a variety of fetal and adult human tissues, but p47/ING1-ALT2 was minimally expressed.

Adult↗
PubMed2000

Detailed deletion mapping of chromosome band 14q32 in human neuroblastoma defines a 1.1-Mb region of common allelic loss.

Neuroblastoma (NB) is a well-known malignant disease in infants, but its molecular mechanisms have not yet been fully elucidated. To investigate the genetic contribution of abnormalities on the long arm of chromosome 14 (14q) in NB, we analysed loss of heterozygosity (LOH) in 54 primary NB samples using 12 microsatellite markers on 14q32. Seventeen (31%) of 54 tumours showed LOH at one or more of the markers analysed, and the smallest common region of allelic loss was identified between D14S62 and D14S987. This region was estimated to be 1-cM long from the linkage map. Fluorescence in situ hybridization also confirmed the loss. There was no statistical correlation between LOH and any clinicopathologic features, including age, stage, amplification of MYCN and ploidy. We further constructed a contig spanning the lost region using bacterial artificial chromosome and estimated this region to be approximately 1.1-Mb by pulsed-field gel electrophoresis. Our results will contribute to cloning and characterizing the putative tumour-associated gene(s) in 14q32 in NB.

Alleles↗
PubMed2000

Effects of amygdala or hippocampus lesion on hypergravity-induced motion sickness in rats.

We examined the effects of amygdala lesion (AL) or hippocampal lesion (HL) on hypergravity-induced motion sickness in rats. Rats do not vomit, but the behavior known as pica, the eating of non-nutritive substances such as kaolin, can be used as an index of motion sickness. In the present study, hypergravity-induced kaolin intake and apomorphine-induced kaolin intake were measured before and after brain lesions. After AL, hypergravity-induced kaolin intake and the ratio of the hypergravity- to apomorphine-induced kaolin intakes were decreased. These results indicate that AL suppressed motion sickness more than pica behavior itself, suggesting that the amygdala plays an important role in the development of motion sickness in rats. Conversely, after HL, hypergravity-induced kaolin intake was increased, as was the ratio of the hypergravity- to apomorphine-induced kaolin intakes. These results indicate that HL aggravates motion sickness induced by hypergravity in rats, suggesting that the hippocampus counteracts motion sickness.

Amygdala↗
PubMed2000

Association of poor prognosis with loss of 12q, 17p, and 18q, and concordant loss of 6q/17p and 12q/18q in human pancreatic ductal adenocarcinoma.

OBJECTIVE: Pancreatic cancer is one of the diseases with the poorest prognosis, but the associated genetic alterations are not yet well understood. The genetic alterations reported to date in pancreatic cancer include frequent mutations of the KRAS, TP53, p16, and SMAD4 genes. Mutation of the TP53 gene was reported to be associated with a poor prognosis. In this study, we analyzed the association of loss of heterozygosity (LOH) with clinicopathological features to attempt to devise effective methods in the future for clinically applying our results to diagnosis and treatment. METHODS: A total of 55 tumors from patients with primary pancreatic ductal carcinomas (34 men and 21 women, mean average age 63.9 yr) in which all the relevant clinical and pathological data were available were analyzed. A total of 46 cases were surgically resected, and nine cases were not. Tumor cells as well as corresponding normal cells were collected by microdissection under a microscope, and DNAs were purified. Allelotype analysis was performed by the PCR-based method, and the results were statistically analyzed. RESULTS: LOH of > or =30% were observed on chromosome arms 17p (47%, 17/36), 9p (45%, 14/31), 18q (43%, 15/35), 12q (34%, 10/29), and 6q (30%, 10/33). LOH of 12q, 17p, and 18q were significantly associated with a poor prognosis. Concordant losses of 6q with 17p and 18q were significantly associated with a poor prognosis. Concordant losses of 6q with 17p and of 12q with 18q were also found. CONCLUSIONS: Because LOH of 12q, 17p, and 18q are significantly associated with a poor prognosis, mutation of the putative tumor suppressor genes on these chromosome arms may play significant roles in the disease progression. Concordant losses of 6q with 17p and of 12q with 18q suggest that protein products of putative tumor suppressor genes on 6q and 12q may function in association with TP53 and SMAD4, respectively.

Alleles↗
PubMed2000

Analysis of the candidate target genes for mutation in microsatellite instability-positive cancers of the colorectum, stomach, and endometrium.

Microsatellite instability (MSI) in human carcinoma DNA is a characteristic phenotype observed in hereditary non-polyposis colorectal cancer and also in some human sporadic cancers including multiple primary carcinomas. In this study, we analyzed mutations in the hCHK1, E2F4, hMSH3, and hMSH6 genes in MSI+ human cancers arising in colorectum, stomach and endometrium. The E2F4 and hMSH3 genes were mutated in all tumor types. Interestingly, the hMSH6 gene was mutated in colorectal and gastric cancers but not in endometrial cancer; this is similar to the TGFbetaRII gene. It is notable that the mutation status of the secondary mutators, hMSH3 and hMSH6, did not influence slippage-related frameshift mutations in genes harboring simple tandem-repeats, which suggests that the MSI phenotype may be affected mainly by abnormalities in the primary mutator genes, not by the secondary mutator genes. No mutations were observed in the cell cycle checkpoint gene hCHK1; mutations of this gene are thought to have a limited role, if any, in at least the tumor types analyzed in this study.

Checkpoint Kinase 1↗
PubMed2000

Not hMSH2 but hMLH1 is frequently silenced by hypermethylation in endometrial cancer but rarely silenced in pancreatic cancer with microsatellite instability.

Disruption of the DNA mismatch repair (MMR) system has been found to play an important role in sporadic human cancers of several organs such as colorectum, stomach, endometrium, and pancreas. In cancers of the former three organs, disruption of the MMR system is mainly caused by hypermethylation of the hMLH1 gene. We investigated the expression of the hMLH1 and hMSH2 proteins immunohistochemically in pancreatic and endometrial cancers with high frequency microsatellite instability (MSI-H). Loss of expression of hMLH1 was found in none of seven pancreatic cancer, whereas eight (57%) of 14 endometrial cancer showed loss of expression of hMLH1. On the other hand, one (14%) of seven pancreatic cancers and two (14%) of 14 endometrial cancers showed loss of hMSH2 expression. We further analyzed the methylation status at the promoter region of the hMLH1 and hMSH2 genes and found hypermethylation of hMLH1 at the promoter region in the great majority of endometrial cancers with loss of expression. However, no pancreatic cancer showed hypermethylation. We then further analyzed 22 pancreatic cancer cell lines and obtained similar results. These results suggested that MSI-H in pancreatic cancer is probably caused by different mechanisms from those of other sporadic cancers with MSI-H.

Adaptor Proteins, Signal Transducing↗
PubMed2000

Frequent loss of copy number on the long arm of chromosome 21 in human esophageal squamous cell carcinoma.

To understand the molecular pathogenesis of human esophageal cancer, we performed a comparative genomic hybridization (CGH) analysis using 10 esophageal squamous cell carcinomas. Frequent gains of 1q, 3q, 7p, 7q, 8q, 11q, and 20q and losses of 3p, 4p, 4q, 5q, 9p, 11p, 11q, 13q, 18q, 21q, and Y were observed. Among these regions, 21q has not yet been investigated in detail. We performed an allelotype study using 55 squamous cell carcinomas of the esophagus and 20 microsatellite markers on 21q and found LOH in 36 cases (65%): 22 (61%) of 36 cases with LOH indicated allelic loss in all informative loci, suggesting loss of the whole chromosome arm 21q, and five smallest regions of overlap were found. Our present results suggest the existence of a tumor suppressor gene(s) that plays a role in the genesis of squamous cell carcinoma of the esophagus.

Chromosome Aberrations↗
PubMed1999

Adenovirus-mediated transfer of p33ING1 with p53 drastically augments apoptosis in gliomas.

The p53 tumor suppressor gene is an important target for the gene therapy of cancers, and clinical trials targeting this gene have been conducted. Some cancers, however, are refractory to p53 gene therapy. Therefore, it has been combined with other therapies, including chemotherapy and radiotherapy, to enhance the cytopathic effect of p53 induction. The p33ING1 gene cooperates with p53 to block cell proliferation. In this study, we investigated whether adenovirus (Adv)-mediated coinduction of p33ING1 and p53 enhances apoptosis in glioma cells (U251 and U-373 MG), which showed no genetic alterations but low expression levels of p33ING1. Although the single infection of Adv for p33ING1 (Adv-p33) at a multiplicity of infection (MOI) of 100, or Adv for p53 controlled by myelin basic protein (MBP) promoter (Adv-MBP-p53), a glioma-specific promoter, at a MOI of 50, did not induce apoptosis in U251 and U-373 MG glioma cells; coinfection of Adv-p33 and Adv-MBP-p53 at the same MOIs induced drastically enhanced apoptosis in both cell lines. Apoptosis was not induced in NGF-treated PC-12 cells infected with a high MOI (300) of Adv-p33 nor in those coinfected with Adv-p33 (100) and Adv-MBP-p53 (50). Coinfection of Adv-p33 and Adv-MBP-p53 demonstrated morphological mitochondrial damage during the initial stage of apoptosis, which likely led to apoptotic cell death. Our results indicate that this coinfection approach can be used as a modality for the gene therapy of gliomas, sparing damage to normal tissues.

Adenoviridae↗