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H Sugimura

Publications and source records attributed to H Sugimura.

At least 19 recordsLinked to original sources
PubMed1998

Evidence that DOCK180 up-regulates signals from the CrkII-p130(Cas) complex.

DOCK180 is one of the two principal proteins bound to the SH3 domain of the adaptor protein CrkII. Here, we have studied the involvement of DOCK180 in integrin signaling. DOCK180 was neither phosphorylated nor bound to CrkII in quiescent NIH 3T3 cells and 3Y1 cells. We found that DOCK180 was phosphorylated and bound to CrkII in NIH 3T3 cells stimulated with integrin and also in 3Y1 cells transformed by v-src or v-crk. The binding of DOCK180 to CrkII correlated with the binding of CrkII to p130(Cas), which is a major CrkII SH2 domain-binding protein at focal adhesions. In a reconstitution experiment, expression of DOCK180 induced hyperphosphorylation of p130(Cas) and a concomitant increase in the amount of CrkII bound to p130(Cas). Similarly, binding of DOCK180 to CrkII was also enhanced by the coexpression of p130(Cas). Finally, we found that coexpression of p130(Cas) and CrkII with DOCK180 induced local membrane spreading and accumulation of DOCK180-CrkII-p130(Cas) complexes at focal adhesions. These findings suggest that DOCK180 positively regulates signaling from integrins to CrkII-p130(Cas) complexes at focal adhesions.

3T3 Cells↗
PubMed1998

Genetic polymorphisms and alternative splicing of the hOGG1 gene, that is involved in the repair of 8-hydroxyguanine in damaged DNA.

The hOGG1 gene encodes a DNA glycosylase that excises 8-hydroxyguanine (oh8Gua) from damaged DNA. Structural analyses of the hOGG1 gene and its transcripts were performed in normal and lung cancer cells. Due to a genetic polymorphism at codon 326, hOGG1-Ser326 and hOGG1-Cys326 proteins were produced in human cells. Activity in the repair of oh8Gua was greater in hOGG1-Ser326 protein than in hOGG1-Cys326 protein in the complementation assay of an E. coli mutant defective in the repair of oh8Gua. Two isoforms of hOGG1 transcripts produced by alternative splicing encoded distinct hOGG1 proteins: one with and the other without a putative nuclear localization signal. Loss of heterozygosity at the hOGG1 locus was frequently (15/ 23, 62.2%) detected in lung cancer cells, and a cell line NCI-H526 had a mutation leading to the formation of the transcripts encoding a truncated hOGG1 protein. However, the oh8Gua levels in nuclear DNA were similar among lung cancer cells and leukocytes irrespective of the type of hOGG1 proteins expressed. These results suggest that the oh8Gua levels are maintained at a steady level, even though multiple hOGG1 proteins are produced due to genetic polymorphisms, mutations and alternative splicing of the hOGG1 gene.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1998

[High-dose methylprednisolone-containing chemotherapy in advanced invasive thymoma--report of three cases].

During the period from May, 1995 to August, 1996, three patients with Stage III or IVa invasive thymoma received chemotherapy consisting of cisplatin, doxorubicin and methylprednisolone (1000 mg on days 1 through 5, and 500 mg on days 6 and 7). The first case, a 55-year-old woman, who underwent extended thymectomy 7 years ago, was found to have a recurrent tumor in the left pleural cavity. The second case, a 38-year-old man, who had first operation 3 years ago, developed recurrent tumor in the right pleural cavity. These two patients were treated with the above regimen as the primary mode of therapy. The third case, a 61-year-old woman, had a thymoma with direct invasion to right upper lobe. The same chemotherapy regimen was employed as the induction chemotherapy. All patients showed a major response to treatment with only a small amount of tumor remaining. The effectiveness of chemotherapy in the treatment of malignant tumors has been recently reported to be at least partly due to induction of apoptosis. Steroids are known to induce apoptosis in normal thymic cells, and thus steroid in chemotherapy regimen against invasive thymoma may enhance the effect of anti-cancer drugs through the induction of apoptosis.

Adult↗
PubMed1998

[A case of the pulmonary thrombosis caused by unilateral pulmonary artery occulusion test].

A 71-year-old male, diagnosed as lung cancer, underwent unilateral pulmonary occulusion test. Through the guidewire, 7.5 Fr thermodilution catheter with occlusion balloon was introduced to the left pulmonary artery from the right internal jugular vein. Heparinized physiological saline solution was injected into the distal site of the occulusion. The occulusion time was 15 minutes. Pulmonary artery pressure and wedge pressure were within normal range. Soon after the examination, the pulmonary arteriogram (PAG) showed the defect of the branch to the lingular segment and the lower lobe. We made a diagnosis of pulmonary thrombosis. Three days after the administration of urokinase and heparin, both pulmonary perfusion scintigram and PAG exhibited the reperfusion to these areas. After the thrombolytic therapy was accomplished, antithrombin III and protein C in the serum showed within normal range. It was possible that the damage on the intima due to the thermodilution catheter or the guidewire and the following blood congestion by the pulmonary artery occulusion caused the thrombosis.

Aged↗
PubMed1998

Gastric plasmacytoma coexistent with plasma cell granuloma in a patient with gastric cancer.

We report a rare case of multiple gastric plasmacytomatous lesions at an early stage found incidentally in a stomach resected because of gastric cancer. The three lesions had different macroscopic features, showing depressed, submucosal, and nodular tumor-forming types. The smallest, a depressed lesion, produced IgG of the lambda and kappa types, and had a plasma-cell granuloma-like appearence, whereas the largest, a submucosal tumor, was formed by the monoclonal proliferation of atypical plasma cells containing IgA-kappa type immunoglobulin, and the nodular lesion exhibited histological features intermediate between those of the other two lesions. From their microscopic features and the profile of immunoglobulin production, we believe that these lesions may represent different stages in the possible course of development of plasmacytoma from the early stage of plasma cell granuloma. All three lesions were located far from the gastric carcinoma and it was unclear whether they had any causal relationship with it.

Adenocarcinoma↗
PubMed1998

Two synchronous solid and cystic tumors of the pancreas.

We report a 17-year-old woman who had two synchronous solid and cystic tumors of the pancreas (SCTP) detected by abdominal echography and computed tomography. There was a 6 x 5 cm mass in the pancreatic body and a 3 x 3 cm mass in the tail, with the two lesions being separate. No distal metastases were detected. The resected tumors consisted of solid and cystic components and both were well demarcated with fibrous capsules. The larger tumor was predominantly solid and the smaller one was mostly hemorrhagic. On microscopy, the tumor cells were small, eosinophilic, and arranged, in part, like pseudorosettes. The tumor cells were immunohistochemically positive for alpha-1 antitrypsin, neuron-specific enolase, and synaptophysin. The final diagnosis was SCTP arising synchronously and independently at two sites. As far as we know, only one case of multicentric SCTP has been reported previously. Local recurrence of SCTP suggests the possibility of multicentric occurrence, and we believe that reports of such cases may increase in the future with advances in echography and computed tomography.

Adolescent↗
PubMed1998

RER phenotype and its associated mutations in familial gastric cancer.

To clarify the genetic background of gastric cancer, we collected 28 familial gastric cancers (FGCs) with reference to the Amsterdam criteria in hereditary non-polyposis colorectal cancer (HNPCC) and investigated the frequency of replication error (RER) at six microsatellite loci and frameshift mutations in its related genes in these tumors. RER was detected in seven (25%) of the 28 gastric cancers. Five (18%) cases showed RER at more than two loci. The apparent increased incidence of RER in FGC was not detected compared with that reported in sporadic gastric cancers previously. Among four cases with RER at more than three loci, frameshift mutations in the (A)8 track of the hMSH3 gene were detected in all the four cases and mutations in the (A)10 track of the transforming growth factor-beta type II receptor (TGF-beta RII) gene were detected in the three of them. Histologically, three of the four cases were of the intestinal type, and the other one was the diffuse type. No mutation was detected in the (C)8 and (GT)3 tracks of the hMSH6 and TGF-beta RII genes respectively. These results indicate that the acquisition of the RER phenotype equally influences the gastric carcinogenesis of both sporadic and familial cases, and that the majority of FGC is pathogenetically distinct from HNPCC.

Adult↗
PubMed1998

Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human gastric cancer.

Mutations in the transforming growth factor beta type II receptor (TGFbetaRII) gene have been detected in several human cancer types exhibiting microsatellite instability. Using intron primers previously reported for examination of the entire coding region of the TGFbetaRII gene, 29 sporadic gastric cancers were screened with non-radioactive single strand conformation polymorphism and subsequent DNA sequencing analysis. Mutations of the TGFbetaRII gene were detected in three out of 29 tumors (10%). Two cases showed deletions in a polyadenine tract in both alleles and was positively associated with replication error. One case had an insertion of GA dinucleotide sequence in one allele. Mutations of the TGFbetaRII gene were restricted to exon 3 and other coding regions were not affected. Loss of heterozygosity was detected by analyzing a polymorphic site in intron 2. Three out of nine (33%) informative cases, which were all of intestinal type and advanced cases, showed loss of heterozygosity but neither TGFbetaRII mutation nor replication error was found in these cases. Immunoreactivity of TGFbetaRII in tumor tissues was reduced to a different extent in the gastric cancer with genetically abnormal transforming growth factor. Although the numbers studied are small, homozygous (A)10 deletion or loss of heterozygosity of TGFbetaRII is involved in tumorigenesis and progression of at least some part of sporadic gastric cancer.

Humans↗
PubMed1998

Genetic alterations of mixed hyperplastic adenomatous polyps in the colon and rectum.

Some mixed hyperplastic adenomatous polyps (MHAPs) contain dysplastic lesions or even carcinomas. These polyps are considered to be different from ordinary hyperplastic polyps and may have a preneoplastic potential. We investigated APC and K-ras mutations in MHAPs of the colon and rectum, and also in colorectal adenomas and hyperplastic polyps to identify molecular differences between MHAPs, adenomas and hyperplastic polyps, using direct sequencing of mutation cluster regions (MCR) in APC and K-ras. No APC mutations were identified in 12 MHAPs and 8 hyperplastic polyps, whereas 10 of 27 (37.0%) adenomas showed somatic mutations. K-ras mutations were identified in one of 12 (8.3%) MHAPs, one of 8 (12.5%) hyperplastic polyps, and 10 of 27 (37.0%) adenomas. p53 mutation was found in a carcinoma arising in an MHAP. Mutations other than APC mutations may play a role in the development of MHAPs.

Adenoma↗
PubMed1998

Infrequent mutations of the hOGG1 gene, that is involved in the excision of 8-hydroxyguanine in damaged DNA, in human gastric cancer.

DNA glycosylase, encoded by the hOGG1 gene, repairs 8-hydroxyguanine (oh8Gua), which is an oxidatively damaged mutagenic base. To clarify whether the DNA repair activity of hOGG1 protein is involved in gastric carcinogenesis, we examined 9 gastric cancer cell lines and 35 primary gastric cancers for mutations and genetic polymorphisms of the hOGG1 gene by polymerase chain reaction-single strand conformation polymorphism analysis. A G-to-A transition was detected in a gastric cancer cell line, MKN1. This nucleotide change caused the conversion of the amino acid from Arg to His at codon 154, which is located in a domain highly conserved among human, mouse, and yeast OGG1 proteins. No mutation was detected in primary gastric cancers. We compared the distribution of the polymorphic alleles associated with enzymatic activity (hOGG1-Ser326 vs. hOGG1-Cys326) between 35 gastric cancer patients and 42 healthy individuals. Although the frequency of the Cys326 allele, associated with low enzymatic activity, in gastric cancer patients was a little higher than that in healthy individuals, the difference did not reach statistical significance. These results suggest that low hOGG1 activity due to mutations and genetic polymorphisms is involved in the development of only a small subset of gastric cancers.

DNA Damage↗
PubMed1998

Transforming growth factor beta type II receptor (TGF beta RII) mutation in gastric lymphoma without mutator phenotype.

A new mutation in the serine-threonine kinase domain of the transforming growth factor beta type II receptor (TGF beta RII) was found in a case of diffuse, B cell non-Hodgkin's lymphoma of the stomach. A missense mutation (ACA to GCA, Thr to Ala) was detected in exon 5, and a wild type allele was also present. This is the first naturally occurring mutation in the kinase domain of this gene identified in human primary lymphoma. The replication error at three loci was negative, and the poly A tract of exon 3, which is frequently a target of mismatch repair genes, was intact. Malignant lymphoma of B cell origin in the stomach is an addition to an expanding catalogue of tumors with TGF beta RII alterations, and the biological sequelae of the change in the functional domain and the clinical characteristics of the patient in this study are intriguing.

Aged↗
PubMed1998

Collagen and elastin synthesis by desmoid tumor in vitro.

In order to characterize human desmoid tumors in vitro, the production of collagen and elastin and the expression of collagen types alpha1(I), alpha1(III) and transforming growth factor (TGF)-beta1 mRNA were investigated in six desmoid tumors; five derived from familial adenomatous polyposis patients and one from a sporadic case. The proportion of collagen production to total protein production was determined by 3H-imino acid incorporation, an indicator of collagen synthesis, using high-performance liquid chromatography (HPLC). The proportion of collagen production to total protein production was much higher in all six desmoid tumors compared with human skin fibroblasts (HSF). Quantitatively, the rate of elastin synthesis in desmoid tumor cells monitored by valine-proline peptide was also significantly higher than in HSF. Pro-alpha1(I) collagen mRNA was highly expressed in both desmoid tumors and HSF at approximately the same level, whereas pro-alpha1(III) collagen mRNA was more abundant in some of the desmoid tumors than the normal skin fibroblastic cell lines. Tumor growth factor-beta1 mRNA, which is believed to stimulate collagen synthesis, was expressed in both desmoid tumors and HSF to the same extent. These results demonstrate the increased formation of collagen and elastin in desmoid tumors in vitro and suggest that the increased synthesis of elastin rather than of collagen and TGF-beta1 may be involved in increased fibrogenesis by desmoid tumors.

Adenomatous Polyposis Coli↗
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↗