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H Sugimura

Publications and source records attributed to H Sugimura.

At least 37 records · Page 2Linked to original sources
PubMed1998

Association of Ile462Val (Exon 7) polymorphism of cytochrome P450 IA1 with lung cancer in the Asian population: further evidence from a case-control study in Okinawa.

Okinawa, a group of islands that lie between the East China Sea and the Pacific Ocean, 2000 km south of the Japanese main islands, has a different profile of diseases, ethnicities, and cultures than does the rest of Japan. We examined an Ile462Val polymorphism (CYP1A1*2 allele) of cytochrome P450 IA1 in a hospital-based case-control study of lung cancer patients (247 cases and 185 controls) in Okinawa to ascertain the association of this variant with lung cancer. In addition, the distribution of this genotype was studied in populations from different areas of Japan, including Tokyo (n = 69) and Iwate (northern part of Japan; n = 81), as well as in a Chinese group from the Jiangsu province (n = 39) and in an Australian Caucasian group (n = 146). Genotype frequency in controls was not significantly different from area to area in Japan. In Okinawa, however, the genotype encoding Val/Val was associated with a significantly higher risk of lung cancer (odds ratio = 3.32, P = 0.013), especially of squamous cell carcinoma and small cell carcinoma (odds ratio = 4.85 and 9.35, respectively). The Val-encoding allele was less frequent in the Chinese population and was rare in Australian Caucasians. Thus, this study gives support to the value of the cytochrome P450 IA1 Ile462Val polymorphism as a practical high-risk marker of lung cancer in populations, especially those in southeast Asia, in which this variant is more common.

Adult↗
PubMed1997

Deficient transforming growth factor-beta1 activation and excessive insulin-like growth factor II (IGFII) expression in IGFII receptor-mutant tumors.

The insulin-like growth factor II receptor (IGFIIR) gene has been identified as a coding region target of microsatellite instability in human gastrointestinal (GI) tumors. IGFIIR normally has two growth-suppressive functions: it binds and stimulates the plasmin-mediated cleavage and activation of the latent transforming growth factor-beta1 (LTGF-beta1) complex, and it mediates the internalization and degradation of IGFII ligand, a mitogen. We used an immunohistochemical approach to determine whether IGFIIR mutation affected expression of these proteins in GI tumors. Four highly specific antibodies were used: LC(1-30), which recognizes the active form of TGF-beta1; anti-LTGF-beta1, which detects the LTGF-beta1 precursor protein; anti-IGFIIR; and anti-IGFII ligand. Twenty GI tumors either with (6 of 20) or without (14 of 20) known IGFIIR mutation were examined, along with matching normal tissues. Results were statistically significant in the following categories: (a) decreased active TGF-beta1 protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues; (b) increased LTGF-beta1 protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues; and (c) increased IGFII ligand protein expression in IGFIIR-mutant tumor tissues versus matching normal tissues or IGFIIR-wild-type tumor tissues. These data suggest that in genetically unstable GI tumors, mutation of a microsatellite within the coding region of IGFIIR functionally inactivates this gene, causing both diminished growth suppression (via decreased activation of TGF-beta1) and augmented growth stimulation (via decreased degradation of the IGFII ligand).

Colorectal Neoplasms↗
PubMed1997

Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors.

The E2F group of transcription factors transactivates genes that promote progression through the G1-S transition of the cell cycle. Members of the retinoblastoma (Rb) family of proteins bind to E2Fs and inhibit this function. E2F-4, one example of the E2F group, functions as an oncogene when transfected into nontransformed cells in vitro. On the other hand, mice that are homozygously lacking a normal E2F-1 gene develop cancers, consistent with a tumor-suppressive role for this gene. The exact function of E2Fs has thus been unclear; moreover, direct involvement of this gene in primary human tumorigenesis has not been shown. We, therefore, investigated mutation within the E2F-4 coding region in 16 primary gastric adenocarcinomas, 12 ulcerative colitis-associated neoplasms, 46 sporadic colorectal carcinomas, 9 endometrial cancers, and 3 prostatic carcinomas. We limited our investigation to the serine repeat within E2F-4, reasoning that this tract might be altered in genetically unstable tumors (replication error-positive, or RER+). All tumors were RER+, with the exception of a control group of 15 RER- sporadic colorectal carcinomas. PCR with incorporation of [32P]dCTP was performed using primers flanking the serine trinucleotide (AGC) repeat. Twenty-two of 59 gastrointestinal tumors (37%) contained E2F-4 mutations; these comprised 5 of 16 gastric tumors (31%), 4 of 12 ulcerative colitis-associated neoplasms (33%, including 1 dysplastic lesion), and 13 of 31 sporadic colorectal cancers (42%). No mutation was present in any of the endometrial, prostate, or RER- colorectal tumors. Of note, homozygous mutations occurred in three cases, and two of seven informative patients showed loss of one E2F-4 allele in their tumors. Furthermore, the RER+ sporadic colorectal tumors were evaluated at trinucleotide repeats within the genes for N-cadherin and B-catenin; no tumors demonstrated mutation of these genes. These data suggest that E2F-4 is a target of defective DNA repair in these tumors.

Adenocarcinoma↗
PubMed1997

Apparent protection from instability of repeat sequences in cancer-related genes in replication error positive gastrointestinal cancers.

Genomic instability at simple repeated sequences has been observed in various types of human cancers and is considered an important mechanism in tumorigenesis. Alterations at microsatellite loci have been reported scattered throughout the genome. Recently, the transforming growth factor-beta receptor type II (TGF-beta RII) and the insulin-like growth factor II receptor (IGF-IIR) genes were shown to have inactivating mutations within coding microsatellite sequences. The demonstration of mutations in two growth regulatory genes supports the idea that other regulatory genes with repeat sequences may also be targets in tumours with defective mismatch repair. We examined genes involved in tumour suppression, cell adhesion and cell cycle regulation for mutations at small repeat sequences in replication error positive gastrointestinal cancers. Several polymorphisms were found which exhibited instability, but no other instability was present in the regions examined.

Activin Receptors, Type I↗
PubMed1997

BRCA2 germline mutations in Japanese breast cancer families.

Germline mutations of BRCA2 were examined in 20 Japanese breast cancer families without BRCA1 mutations, including one demonstrating cancer development in a male. Three different mutations, resulting in truncation of the BRCA2 protein, were detected in 3 different families. They were 9474insA (exon 24, termination at codon 3110), C8729A (exon 20, S2834 ter) and 982del4 (exon 9, termination at codon 275). The 982del4 mutation was detected in the family with a case of male breast cancer. Age at onset was young, with a range of 28-43 years, in the 2 female breast cancer families with truncation mutations. One probable missense mutation, A10462G (13412V), was further detected in 2 families, although cosegregation of this allele with the breast cancer phenotype was not complete. The rate of BRCA2 mutations in Japanese families was suggested to be almost the same as in Western countries, and larger than it is the case for BRCA1.

Adult↗
PubMed1997

Expression of high-mobility group-1 mRNA in human gastrointestinal adenocarcinoma and corresponding non-cancerous mucosa.

An 1194-nucleotide complementary DNA clone, FM1, encoding a human high-mobility group-1 protein (HMG-1) was isolated from a well-differentiated human gastric-carcinoma cell line complementary DNA library by a differential screening method. FM1 is similar to the published human HMG-1 in mature protein, with only 3 different codons at positions 11, 149, and 190. We analyzed 33 gastric and colorectal adenocarcinomas for expression of the FM1 gene. Northern-blot analysis revealed that all of the cancers expressed FM1 at a higher level than in corresponding non-cancerous mucosa, with 2 transcripts of approximately 1.4 and 2.4 kilobases. The FM1 expression level in the non-cancerous tissues increased with the depth of accompanying cancer invasion. Only 18.2% of well-differentiated cancers showed a higher expression level in corresponding non-cancerous tissues, whereas the expression in corresponding non-cancerous tissues was significantly higher in moderately (60%) and poorly differentiated (83.3%) cancers. In situ hybridization demonstrated the location of FM1 mRNA in well- and poorly differentiated gastric-cancer cells as well as in non-cancerous tissue adjacent to poorly differentiated gastric cancer, but no hybridization was detected in normal epithelial cells adjacent to well-differentiated gastric cancer. These findings may provide new information on HMG-1 mRNA expression in human gastrointestinal cancer and suggest a correlation between FM1 mRNA expression to the differentiation and the stage of human gastrointestinal adenocarcinomas.

Aged↗
PubMed1997

Mutation of hMSH3 and hMSH6 mismatch repair genes in genetically unstable human colorectal and gastric carcinomas.

Mutations within microsatellite sequences, consisting of additions or deletions of repeat units, are known as the replication/repair error positive (RER+) phenotype or micorsatellite instability (MI). Microsatellite instability has been demonstrated in hereditary and sporadic colorectal carcinomas and is usually observed in noncoding regions of genomic DNA. However, relatively few coding region targets of MI have been identified thus far. Using PCR, we amplified regions encompassing (A)8 and (C)8 microsatellite tracts within hMSH3 and hMSH6 from 31 RER+ sporadic colorectal tumors, 8 hereditary colon cancers, 23 RER+ gastric carcinomas, and 32 RER- gastric tumors. Mutations were found in 11 (36%) of 31 sporadic colon carcinomas, 4 (50%) of 8 hereditary colorectal cancers, and 5 (22%) of 23 RER+ gastric carcinomas, but in only 2 (6%) of 32 RER- gastric carcinomas. These frameshift mutations cause premature stop codons downstream that are predicted to abolish normal protein function. Our results and those of others suggest that DNA mismatch repair genes, such as hMSH3 and hMSH6, are targets for the mutagenic activity of upstream mismatch repair gene mutations and that this enhanced genomic instability may accelerate the accumulation of mutations in RER+ tumors.

Adenocarcinoma↗
PubMed1997

8-hydroxyguanine (7,8-dihydro-8-oxoguanine) DNA glycosylase and AP lyase activities of hOGG1 protein and their substrate specificity.

Recently we cloned a structural human homolog (hOGG1) of the yeast OGG1 (yOGG1) gene that is involved in the excision repair of 8-hydroxyguanine (also known as 7,8-dihydro-8-oxoguanine; oh8Gua), hOGG1 protein shares 38% amino acid identity with yOGG1 protein. In this paper, we define the substrate specificity of oh8Gua DNA glycosylase and AP lyase activities of the hOGG1 protein. The oh8Gua released from oh8Gua containing DNA was measured by analysis with HPLC coupled with electrochemical detector (ECD) and cleavage sites in the DNA were identified by cleavage assay using gel electrophoresis. GST-hOGG1 protein possessed the oh8Gua DNA glycosylase/AP lyase activity and weak delta-elimination activity, oh8Gua opposite the C in duplex oligonucleotide was most efficiently released by GST-hOGG1 protein and oh8Gua opposite the T was also released, while oh8Gua opposite the G or A was very slowly done. The rank order of DNA cleavage efficiency was the same as that of oh8Gua glycosylase activity. Glycosylase/AP lyase activities and their substrate specificities of the GST-hOGG1 protein was similar to GST-yOGG1 protein but different from MutM protein. These results indicate that the dominant function of hOGG1 protein is a oh8Gua glycosylase reaction by specifically recognizing oh8Gua and pyrimidine opposite the oh8Gua and delta-elimination reaction in the same manner as yOGG1 protein. Thus, the hOGG1 gene is a functional human homolog of the yOGG1 gene on oh8Gua excision repair in spite of the low structural identity at amino acid level between hOGG1 and yOGG1 proteins.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1997

Origin of intraepithelial apoptotic cells in human colorectal adenomas.

The origin of intraepithelial apoptotic cells in human colorectal adenomas was examined using immunohistochemistry. Tissue sections of human colorectal adenomas obtained during surgery or endoscopy were stained by the streptavidinbiotin method using antibodies against carcinoembryonic antigen (CEA) and leukocyte common antigen (LCA). Approximately 15.7% of apoptotic bodies stained positive for CEA with immunoreactivity on the cytoplasm, whereas all cells stained negative for LCA. These findings suggest that intraepithelial apoptosis in human colorectal adenomas originates from adenoma cells rather than infiltrating lymphocytes as previously proposed, and that apoptotic cells maintained their cytoplasmic antigenicity in the early stages of apoptosis.

Adenoma↗
PubMed1997

p53 overexpression and proliferative activity do not correlate with lymph node metastasis in early gastric cancer.

We investigated p53 overexpression and the proliferative activity of the primary lesion as well as the clinicopathological features of 75 patients with gastric cancer invading the submucosa (sm cancer), of whom 14 (18.7%) had lymph node metastasis. Among the clinicopathologic features studied, only lymphatic invasion by the primary tumor was related to lymph node metastasis. There was no relationship between immunohistochemical staining for p53 protein or Ki-67 and lymph node metastasis. The p53-positive rate was 35.7 and 57.1% in patients with and without metastasis, respectively, while the mean Ki-67 labeling index was 38.9 and 38.1%, respectively. Our results suggest that p53 mutation or the proliferative activity of sm cancer do not influence lymph node metastasis, even though p53 mutation may enhance the proliferative activity and metastatic potential of advanced gastric cancer.

Adenocarcinoma↗
PubMed1997

[Microsatellite instability in gastric cancer with varied structure].

BACKGROUND: The intratumoral histological heterogeneity of cancer has been investigated by many pathologists. Although microsatellite alteration has been reported in gastric cancer, the significance of genomic instability in these histologically heterogeneous cases has not been elucidated. METHODS: Microsatellite alteration detected by polymerase chain reaction (PCR) in 13 primary advanced gastric cancers with varied structure was examined at 8 microsatellite loci. RESULTS: We were able to detect a greater prevalence of replication errors (RER) (6/13, 46.2%) at the primary site of gastric cancer than previously reported and loss of heterozygosity (LOH) at 17p (4/13, 30.8%) was demonstrated at the primary sites. All the same time, we also examined metastatic tumors in the regional lymph nodes in 12 of these cases. The frequency of RER (8/12, 66.7%) in metastatic lesions was higher than that in primary tumors. Detectability of RER was more frequent in the poorly differentiated portions than the well-differentiated portions of lymph node metastases. CONCLUSIONS: These findings suggest that gastric cancer with varied structure acquired frequent microsatellite instability during progression and metastasis, and we reasoned that the mutator phenotype detected by microsatellite alterations may represent heterogeneous tumor clones in gastric cancer and lymph node metastases.

Adenocarcinoma↗
PubMed1997

Stage-dependent evaluation of microsatellite instability in gastric carcinoma with familial clustering.

Familial clustering of gastric cancer is probably caused by multifactorial processes, both environmental and genetic. In this report, the incidence of microsatellite instability (MSI) in 31 cases of gastric cancer in Japanese (33 lesions) with familial clustering (two or more gastric cancers within second-degree relatives) was compared to MSI in Japanese cases without a family of any cancer in age ( +/- 10 years)-, stage-, and histological subtype-matched case-control study. Although the difference noted was not significant, we noted a strong trend for MSI at any of up to seven loci of CA repeats to occur more frequently in the patients with a family history of gastric than in the control patients in early cancer (intramucosal and submucosal), whereas the prevalence of MSI was similar in both groups in more advanced cases, in which the tumor invaded beyond the proper muscle layer of the gastric wall. Because the contribution of a family history of gastric cancer to MSI apparently differs in early and advanced gastric cancer, interpretation of MSI in familial gastric cancer cases published previously require reevaluation in terms of stage and proper controls. An acquisition of CA repeat alterations in the early stage rather than in the late stage of gastric carcinogenesis may have in common etiological factors, at least in some cases, with the familial clustering of gastric cancer.

Adult↗
PubMed1996

Identification of cytokeratin subspecies altered in rat experimental esophageal tumors by subtractive cloning.

By using the subtractive hybridization method, two complementary DNA clones differently expressed in rat normal esophageal epithelium and squamous cell carcinoma induced by administration of precursors of N-nitrososarcosine ethyl ester were isolated. A rat homologue of the human 50-kDa type I cytokeratin 14 was cloned for the first time and shown to be expressed preferentially in squamous cell papillomas and carcinomas, whereas it was weakly expressed or absent in normal squamous epithelial cells and in hyperplastic lesions. A rat homologue of the mouse 57-kDa type II cytokeratin showed strong expression in both normal and tumor tissues. These results are well consistent with the reported alteration of keratin subspecies in human esophageal cancers, therefore, encouraging us to use this experimental system as a model for human esophageal carcinogenesis.

Animals↗
PubMed1996

Expression of structure-specific recognition protein mRNA in fetal kidney and Fe-nitrilotriacetate-induced renal carcinoma in the rat.

Specific expression of the structure-specific recognition protein (SSRP) gene was investigated in rat fetal, adult, and tumor tissues using a 2.0-kb partial sequence of rat SSRP cDNA isolated from a cDNA library of rat renal cell carcinoma. The results revealed that it was rather specifically expressed in rat fetal kidney and renal cell carcinoma induced by Fenitrilotriacetate, but not in adult kidney, when various organs were tested by Northern blot analysis. In situ hybridization further demonstrated that it was located in the neoplastic cells of renal cell carcinoma and in the epithelial cells of fetal kidney but undetectable in any cells of normal adult kidney. These observations seem to imply the involvement of SSRP gene, which is believed to recognize structural alterations of DNA, in kidney development and carcinogenesis of certain types of kidney cancer.

Animals↗
PubMed1996

Predominant expression of human zic in cerebellar granule cell lineage and medulloblastoma.

Zic is a novel zinc finger protein which displays a highly restricted expression pattern in the adult and developing mouse cerebellum and is highly homologous to the recently cloned Drosophila pair-rule gene Opa. To clarify the mechanism for the development of the human cerebellum and its involvement in human nervous system diseases, we have isolated human Zic cDNA and examined its expression by using monoclonal antibody against recombinant Zic protein. The nucleotide sequence of human Zic cDNA is 85% homologous to that of mouse Zic cDNA. Its putative amino acid sequence is highly conserved (> 99%) except for substitution of only two amino acid residues. In situ chromosome hybridization localized the human Zic gene to chromosome band 3q24. Human Zic protein was immunohistochemically detected in the nuclei of the cerebellar granule cell lineage from the progenitor cells of the external germinal layer to the postmigrated cells of the internal granular layer. Furthermore, Zic protein was detected in medulloblastoma (26/29 cases), whereas no other tumors examined (over 70 cases including primitive neuroectodermal tumors) expressed this protein. These findings suggest that Zic is a potential biomarker for medulloblastoma as well as the human cerebellar granule cell lineage.

Adolescent↗
PubMed1996

Localization of Menkes gene expression in the mouse brain; its association with neurological manifestations in Menkes model mice.

Menkes gene (Mc1 or MNK, encoding putative copper-transporting ATPase) expression was investigated and compared in normal and macular mutant mouse brain. Northern blot analysis showed a distinct 8.3-kb transcript and no obvious difference in size or extent in normal mice and macular mutants on postnatal days 0, 4, 7, 10 or 13. In situ hybridization revealed that certain specific populations of cells in the brain express Menkes mRNA, and that their localization in normal and mutant mice did not differ and was conserved on days 4, 10 and 13. The most intense hybridization signals were observed in the hippocampal CA1 region and dentate gyrus, the olfactory bulb nuclei, the cerebellar granular cell layer, the choroid plexus and the ependyma, with less intense signals in the hippocampal CA3 region and cerebellar Purkinje cells. In addition, necrotic neuronal cell death was predominantly observed in the CA3 region and the Purkinje cells of macular mice after postnatal day 10. The finding that the regions that had lower expression level of Menkes mRNA corresponded to those showing neuronal necrosis suggests that the Menkes gene may be responsible for the neuronal degeneration in some specific portions of the brain and clinical manifestations in this mutant.

Adenosine Triphosphatases↗