Carcinogenesis: The more we seek to know the more we need to know - Challenges in the post Genomic Era.
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Journal Article↗
Biomedical subjects
Yutaka Kohgo
Publications and source records attributed to Yutaka Kohgo.
Cell kinetics and genetic instabilities in differentiated type early gastric cancers with different mucin phenotype.
To clarify the biological impact and molecular pathogenesis of cellular phenotype in differentiated-type gastric cancers (DGCs), we investigated cell kinetics and genetic instabilities in early stage of DGCs. A total of 43 early gastric cancers (EGCs) were studied. EGCs were divided into 3 phenotypic categories: gastric (G type, n = 11), ordinary (O type, n = 20), and complete intestinal (CI type, n = 12) based on the combination of HGM, ConA, MUC2, and CD10. Proliferative index (PI), apoptotic index (AI), and p53 overexpression were investigated by immunohistochemical staining with anti-Ki-67, the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling method, and p53 antibody, respectively. Using a high-resolution fluorescent microsatellite analysis system, microsatellite instability (MSI) and loss of heterozygosity (LOH) were examined. Frameshift mutation analysis of transforming growth factor-beta type II receptor (TGF-betaRII) and bcl-2-associated X (BAX) in cancers with MSI was also performed. The mean AI/PI ratio values were 0.04 for G-type, 0.10 for O-type, and 0.13 for CI-type cancers--significantly lower in G type than in O and CI types (P = 0.02 and P = 0.001, respectively). No difference in the incidence of MSI and LOH was seen among the 3 cellular phenotypes. However, the major pattern of MSI, which showed drastic and widely dispersed changes and is related to an increased risk for cancer, was significantly higher in G and O types than in CI type (P <0.005). No frame shift mutations of TGF-betaRII or BAX were found in CI-type cancers. These results indicate that G-type cancers are likely to show more aggressive behaviors than CI-type cancers, and that O-type cancers show the intermediate characteristics of both types. However, the molecular pathogenesis of each phenotypic cancer is not associated with microsatellite alterations.
Adenocarcinoma↗
Ethanol induces transforming growth factor-alpha expression in hepatocytes, leading to stimulation of collagen synthesis by hepatic stellate cells.
BACKGROUND: Liver fibrosis often develops in alcoholic liver diseases without accompanying inflammation; however, the underlying mechanism is unclear. Using ethanol-exposed human HepG2 hepatoblastoma cells as a model for alcoholic liver diseases, we previously found that ethanol exposure causes HepG2 cells to secrete an approximately 6,000 Da nonheparin-binding polypeptide that stimulates collagen synthesis in human IMR-90 fibroblasts. The aim of the current study was to characterize and identify this factor. METHODS: Concentration of type I procollagen peptide and transforming growth factor (TGF)-alpha was assessed by enzyme-linked immunosorbent assay. TGF-alpha protein expression was examined by Western blot. Type I collagen messenger RNA expression in rat hepatic stellate cells was assessed by reverse transcription-polymerase chain reaction. RESULTS: The collagen-stimulating activity in conditioned media from ethanol-exposed HepG2 cells to stimulate type I procollagen peptide synthesis of IMR-90 cells was specifically inhibited by addition of anti-TGF-alpha antibodies. Western blot analysis showed increased TGF-alpha protein expression in ethanol-treated HepG2 cells. TGF-alpha in conditioned medium from ethanol-exposed HepG2 cells stimulated type-I collagen messenger RNA expression in rat hepatic stellate cells. CONCLUSIONS: These results suggest that TGF-alpha derived from ethanol-exposed hepatocytes may contribute to the development of hepatic fibrosis in alcoholic liver diseases.
Blotting, Western↗
PPAR gamma ligand-induced apoptosis through a p53-dependent mechanism in human gastric cancer cells.
We have recently demonstrated that the PPAR gamma ligand troglitazone induced cell growth arrest and evoked apoptosis in a gastric cancer cell line, MKN-45. Since in general, p53 plays an important role in the induction of apoptosis and growth inhibition, we tried to clarify whether or not p53 mediates troglitazone-induced apoptosis and growth arrest in gastric cancer cells. Troglitazone increased the number of apoptoic cells in MKN-28, MKN-45 and MKN-74, but not in KATO-III cells. The troglitazone-induced apoptotic change was significantly reduced by coincubation with bisphenol A digycidyl ether (BADGE), a synthetic PPAR gamma antagonist, in MKN-74 cells, suggesting that PPAR gamma mediates the apoptotic effect of troglitazone. Since KATO-III lacks the p53 gene, we speculated that p53 might be implicated in the PPAR gamma ligand-induced apoptosis. Western blot analysis revealed that p53 expression was increased by troglitazone in a time-dependent manner in MKN-74 cells, further suggesting that p53 may mediate the apoptotic process induced by troglitazone. We next established a dominant-negative p53 mutant by stable transfection of p53 mutant into MKN-74 cells. In the dominant-negative p53 mutant cells, troglitazone failed to induce apoptosis, strongly supporting the hypothesis that p53 indeed mediates the process of the troglitazone-induced apoptosis. In the dominant-negative p53 mutant cells, troglitazone significantly induced cell growth arrest and increased expression of p27(Kip1) protein, which is thought to be the key molecule to evoke growth arrest, suggesting that p53 is not involved in the growth inhibition by troglitazone. All these results suggest that p53 mediates the PPAR gamma ligand-induced apoptosis, but not the cell growth inhibition.
Antineoplastic Agents↗
Leukocytapheresis for treatment of IBD.
The recent development of effective and safe devices to remove leukocytes selectively from circulating blood has facilitated the application of leukocytapheresis for the treatment of inflammatory bowel disease (IBD). Successful results of preliminary trials of leukocytapheresis for IBD led to several nationwide multicenter clinical trials in Japan. As a result, five or six consecutive leukocytaphereses, which were undergone weekly, improved both symptoms and endoscopic findings in approximately 60%-80% of patients with ulcerative colitis (UC). In Japan, leukocytapheresis is now considered to be one of the standard treatments for UC patients with refractory disease to avoid surgery. Here, the current status of indications and mechanisms of action on UC are analyzed by reviewing the results of Japanese multicicenter trials, and the possible application for Crohn's disease is also discussed.
Adult↗
Quantitative analysis for human glucocorticoid receptor alpha/beta mRNA in IBD.
We have previously reported that in peripheral blood mononuclear cells (PBMC), the augmented expression of the beta isoform of the human glucocorticoid receptor (hGRbeta), as a putative dominant negative regulator of glucocorticoid action, is associated with glucocorticoid (GC) unresponsiveness of UC patients. In this study, we quantified the levels and serial changes of hGR transcripts in PBMC of IBD patients by a real-time fluorescence monitoring of PCR. As results, relative hGRbeta mRNA expression was significantly higher in the active stage of UC than in inactive periods of UC or CD patients. Longitudinal analysis revealed that hGRbeta mRNA expression in UC was increased after the relapse of inflammation, suggesting that the overproduction of cytokines during inflammation may be responsible. In in vitro culture experiments of human lymphoid cell (CEM) and human PBMC, IL-7, and IL-18 increased hGRbeta mRNA expression in these cells but GC itself did not. Through these analyses, it is indicated that the inflammatory cytokines altered the splicing condition of the primary transcript of hGR gene in IBD patients.
Adult↗
gamma-Carboxyglutamic acid content of hepatocellular carcinoma-associated des-gamma-carboxy prothrombin.
Serum des-gamma-carboxy prothrombin (DCP) is a useful marker for the diagnosis of hepatocellular carcinoma (HCC), but the exact mechanism of its synthesis and its structural properties in liver diseases are unknown. DCP is measured by the monoclonal antibody MU-3. The purpose of this study was to examine the epitope of MU-3 and to characterize the differences in DCP between HCC and benign liver diseases. The epitope of MU-3 was examined by ELISA using prothrombin Gla domain polypeptides and was determined to be amino acid residues 17-27 of the prothrombin Gla domain, which has four gamma-carboxyglutamic acid residues (Gla) at positions 19, 20, 25 and 26. Peptides having a glutamic acid residue (Glu) at these positions reacted strongly to MU-3 but lost reactivity when Glu 19 or 20 was changed to Gla. In the order of gamma-carboxylation, MU-3 reacted strongly to DCP containing 0-1 Gla, weakly to 2-4 Gla and not at all to DCP containing more than five Gla. After adsorbing normal prothrombin with barium carbonate, DCP reaction to MU-3 was measured by determining the amount of DCP that was adsorbed by MU-3-coated beads. The proportion of DCP reacting to MU-3 in HCC was 41.0-76.8%, whereas in patients with benign liver diseases, only 0-42.1% reacted to MU-3. These results indicate that DCP variants preferentially synthesized in HCC have less than four Gla, which are restricted to positions 16, 25, 26 and 29, whereas DCP variants in benign liver diseases have more than five Gla.
1-Carboxyglutamic Acid↗
Transferrin receptor in tissue and serum: updated clinical significance of soluble receptor.
The transferrin receptor is an essential component of cellular uptake of iron, and it binds to serum transferrin. Recently, 2 different types of transferrin receptors have been recognized: transferrin receptor (TfR or transferrin receptor 1) and transferrin receptor 2. Most cells possess a ubiquitous system controlling the biosynthesis of TfR at the posttranscriptional level to avoid excess iron influx into the cells through TfR. During the process of recycling of transferrin receptors, some are shed and appear as soluble or serum transferrin receptors. Measurement of serum transferrin receptor is a new marker of iron metabolism that reflects body iron stores and total erythropoiesis. It has been shown that serum transferrin receptor to ferritin ratios have significant predictive value for differentiating iron deficiency anemia from non-iron deficiency anemia, such as anemia of chronic disorders, whereas serum ferritin is the only significant independent predictor of iron deficiency anemia.
Anemia, Iron-Deficiency↗
Genetic and phenotypic polymorphisms of the A subunit of Coagulation factor XIII in Japanese population.
To clarify whether genetic polymorphisms in exon 14 of Coagulation factor XIII A-subunit gene (FXIIIA) affect phenotype expressions, we studied genetic polymorphisms in exon 14 of FXIIIA in a Japanese population and the relationship between the genetic polymorphisms and phenotype expression. Genetic polymorphisms in exon 14 of FXIIIA of 144 unrelated Japanese were analyzed by single-strand conformation polymorphism. Plasma FXIIIA antigen concentrations, FXIII activities, and phenotype were also determined by two-dimensional electrophoresis. The frequencies of the three genotypes, the homozygote (AD), the homozygote (BC) and the heterozygote (AD/BC), were 77.1, 0.7, and 22.2%, respectively. The gene frequencies of AD and BC were 0.88 and 0.12. We detected AD (GTT x GAG) and BC (ATT x CAG) at codon 650 and 651 of exon 14. There were no significant differences of FXIIIA antigen concentrations and FXIII activities between these genotypes. We detected three pl differences among them as being pls of 5.3, 5.6, 5.8 in the homozygote (AD) and the heterozygote (AD/BC), and a pl of 5.8 in the homozygote (BC). These polymorphisms affected isoelectric mobility, but did not affect protein levels, enzyme activities, or the molecular weight of FXIII.
Electrophoresis, Gel, Two-Dimensional↗
High-frequency probe EUS-assisted endoscopic mucosal resection: a therapeutic strategy for submucosal tumors of the GI tract.
BACKGROUND: The aim of this study was to evaluate the efficacy and safety of high-frequency probe EUS (HFPE)-assisted endoscopic mucosal resection in the management of submucosal tumors of the GI tract. METHODS: HFPE-assisted endoscopic mucosal resection was attempted in 28 patients with submucosal tumors less than 2 cm in diameter. HFPE was performed with a 20-MHz "through-the-scope" probe. Saline solution was injected into the submucosa. After confirming detachment of the lesion from the muscularis propria by repeat HFPE, endoscopic mucosal resection was performed with a lift-and-cut or endoscopic mucosal resection cap technique. Follow-up endoscopy was performed in all patients. RESULTS: Submucosal tumors from the following areas were included: esophagus 3, stomach 4, duodenum 3, and colon 18. The submucosal tumors were located in the upper third (n = 3), middle third (n = 18), and lower third (n = 7) of the submucosa. Twenty-one submucosal tumors were removed by the lift-and-cut technique and 6 by the cap method. One patient required surgical resection after unsuccessful endoscopic mucosal resection. The origin and depth of penetration of all lesions was accurately depicted by HFPE. Median tumor diameter was 9 mm (range 3-20 mm). Resection was successful and complete in 93% of the cases. There were no immediate postprocedure complications (exact 95% CI [0%, 12.3%]). During a median follow-up of 21.5 months (range 2-74 months) no recurrence was found. CONCLUSIONS: HFPE-assisted endoscopic mucosal resection is safe and effective for the management of selected submucosal tumors of the GI tract. A management algorithm based on endoscopic and HFPE findings is proposed.
Adult↗
Minute findings by magnifying colonoscopy are useful for the evaluation of ulcerative colitis.
BACKGROUND: Colonoscopy has an important role in the diagnosis of ulcerative colitis. However, colonoscopic findings are inadequate for the prediction of relapse without histologic examination. In this study, the role of magnifying colonoscopy in ulcerative colitis was evaluated. METHODS: One hundred sixteen magnifying colonoscopy observations were made in 61 patients with ulcerative colitis between January 1994 and October 1998. A simple classification of magnifying colonoscopic findings into 5 categories was devised as follows: regularly arranged crypt openings, villous-like, minute defects of epithelium, small yellowish spots, and coral reef-like appearance. The colonoscopic findings by classification were compared with histopathologic findings, and the usefulness of the classification for predicting relapse was prospectively analyzed in 18 patients. RESULTS: Compared with grade as determined by conventional colonoscopy, there was a better correlation between the classification of findings by magnifying colonoscopy and histopathologic findings (r(2) = 0.665, 0.807, respectively). Of 18 patients studied prospectively, 7 of 9 with minute defects of epithelium relapsed within 6 months, and the cumulative nonrelapsing rate was significantly lower in patients with minute defects of epithelium compared with those without minute defects of epithelium (p = 0.0059). Moreover, minute defects of epithelium was found to be a significant independent predictive factor for relapse (multivariate analysis, Cox proportional hazards model; p = 0.0203). CONCLUSIONS: Our proposed classification of magnifying colonoscopic findings in patients with ulcerative colitis is useful for the evaluation of disease activity and for the prediction of periods of remission.
Adolescent↗
Up-regulation of transferrin receptor expression in hepatocytes by habitual alcohol drinking is implicated in hepatic iron overload in alcoholic liver disease.
BACKGROUND: Hepatic iron overload is often seen in alcoholic liver disease (ALD). We previously reported that the expression of 4-hydroxy-2-nonenal-protein adducts, which is a lipid peroxidative product and can be used as a marker of radical-mediated cellular damage, was increased in iron-overloaded hepatocytes with ALD. However, the mechanism of hepatic iron overload in ALD has not been clarified. In this study, to elucidate the mechanism of hepatic iron overload in ALD, we immunohistochemically investigated the expression of transferrin receptor (TfR), which mainly acts for cellular iron uptake. METHODS: Hepatic tissues were obtained from 31 patients with ALD and 5 normal livers by percutaneous needle biopsy under laparoscopy or ultrasound guidance. Chemical detection of hepatic iron accumulation was performed by Perls' Prussian blue stain. Immunohistochemical detection of TfR expression was done using human monoclonal anti-TfR antibody (TR104) according to the avidin-biotin complex method with alkaline phosphatase. RESULTS: Excess iron accumulation was found in 22 hepatic tissues with ALD but not in any normal hepatic tissues. TfR expression was increased in hepatocytes of 18 hepatic tissues with ALD but was not detected in any normal hepatic tissues. The mean duration of abstinence of patients who demonstrated positive TfR expression in hepatocytes was significantly shorter than that of patients who demonstrated negative TfR expression (positive: 14 days; negative: 30 days). However, total ethanol consumption, daily ethanol intake, and serum aspartate aminotransferase and gamma-glutamyl transpeptidase values on admission were not significantly correlated with TfR expression in hepatocytes. CONCLUSIONS: The up-regulation of TfR expression in hepatocytes is implicated in hepatic iron overload in ALD, and habitual alcohol drinking is an important factor for the induction of TfR expression.
Alcoholism↗
Troglitazone induces G1 arrest by p27(Kip1) induction that is mediated by inhibition of proteasome in human gastric cancer cells.
We examined in the present study whether human gastric cancer cells express peroxisome proliferator-activated receptor gamma (PPARgamma), the effect of PPARgamma activation by troglitazone, a selective ligand, on cellular growth, and the mechanism of the growth arrest by troglitazone in gastric cancer cells. RT-PCR, northern blot and western blot analysis demonstrated that all four tested human gastric cancer cell lines, MKN-28, MKN-45, MKN-74 and KATO-III, expressed PPARgamma mRNA and protein. WST-1 assay and flow cytometric analysis revealed that troglitazone inhibited the growth and induced G1 arrest in all four gastric cancer cell lines. To examine the role of p27(Kip1), a cyclin-dependent kinase inhibitor, in the G1 arrest by troglitazone, we determined p27(Kip1) protein expression by western blot analysis in gastric cancer cells that had been treated with troglitazone. Troglitazone increased p27(Kip1) in all four gastric cancer cell lines. Since it has been reported that the ubiquitin-proteasome system plays a vital role in the degradation of p27(Kip1) protein, we evaluated the hypothesis that inhibition of proteasome mediates the troglitazone-induced p27(Kip1) accumulation. Lactacystin, a proteasome inhibitor, inhibited cell growth and increased p27(Kip1) expression in MKN-74 cells. It was further demonstrated that troglitazone inhibited proteasome activity in a dose-dependent manner in MKN-74 cells. All these results suggest that troglitazone inhibited proteasome activity, followed by induction of p27(Kip1), which arrests cells at the G1 phase of the cell cycle in gastric cancer cells. The troglitazone-mediated inhibition of the proteasome suggests a novel mechanism for the anti-proliferative effect of this agent in cancer cells.
Antineoplastic Agents↗
Natural history of colorectal nonpolypoid adenomas: a prospective colonoscopic study and relation with cell kinetics and K-ras mutations.
OBJECTIVE: Serial colonoscopic observations were prospectively conducted to elucidate the natural history of nonpolypoid tumors. Furthermore, to clarify whether cell kinetic status affects the tumor development, proliferative indices, apoptotic indices, and K-ras codon 12 point mutations on biopsy specimens were investigated. METHODS: Seventy-five colorectal tumors, 13 polypoid and 62 nonpolypoid type (56 flat elevated and six depressed type) were studied. Proliferating and apoptotic cells were detected with anti-Ki-67 antibody and the terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling method, respectively. Point mutations at K-ras codon 12 were examined by enriched polymerase chain reaction-based restriction fragment length polymorphism assay. RESULTS: The average follow-up period was 22 months (range 1-50). The lesions of subsequent exophytic growth, unchanged shape, depressed growth, and disappearance were observed in 0%, 92%, 0%, and 8% of polypoid type, in 39%, 39%, 13%, and 9% of flat elevated type, and in 33%, 67%, 0%, and 0% of depressed type, respectively. There was no significant difference in tumor size between initial and follow-up colonoscopy. Nonpolypoid tumors apparently changed to the exophytic growth during 2 yr or more. The tumors with exophytic growth had significantly higher proliferative indices/apoptotic indices ratios than those with unchanged morphology and disappearance/depressed growth (p < 0.05, respectively). K-ras codon 12 point mutations did not correlate with tumor development. CONCLUSIONS: Cell kinetic status plays an important role in determining minute colorectal tumor development, but not K-ras codon 12 mutations. Minute nonpolypoid adenomas frequently tend to grow slowly, and nearly 40% of those become the exophytic growth with time. Most of minute nonpolypoid tumors seem to follow the adenoma-carcinoma sequence.
Adenoma↗
Ratio of transferrin (Tf) to Tf-receptor complex in circulation differs depending on Tf iron saturation.
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Anemia↗
[Two cases of stage IV type 4 gastric cancer with good response to TS-1].
We report two patients with Type 4 gastric cancers having multiple lymph node metastasis and carcinomatosa which responded well to TS-1. After administration of TS-1 orally for two courses, both patients showed improved extension of the gastric wall and almost complete reduction of metastatic lymph nodes. In case 2, colonic stenosis due to peritonum carcinomatosa disappeared after chemotherapy with TS-1. Total gastrectomy was performed in both patients in accordance with their wishes. It was confirmed histopathologically that TS-1 was effective against the primary sites and lymph node metastasis. Both patients are well without recurrence and continue taking TS-1.
Antimetabolites, Antineoplastic↗