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Hirotoshi Kikuchi

Publications and source records attributed to Hirotoshi Kikuchi.

10 recordsLinked to original sources
PubMed2006

Up-regulation of GPR48 induced by down-regulation of p27Kip1 enhances carcinoma cell invasiveness and metastasis.

A reduced expression level of the cyclin-dependent kinase inhibitor p27(Kip1) is associated with increased tumor malignancy and poor prognosis in individuals with various types of cancer. To investigate the basis for this relation, we applied microarray analysis to screen for genes differentially expressed between p27(+/-) and parental (p27(+/+)) HCT116 human colon carcinoma cells. Expression of the gene for G protein-coupled receptor 48 (GPR48) was increased in the p27(+/-) cells. Forced expression of GPR48 increased both in vitro invasive activity and lung metastasis potency of HCT116 cells. In contrast, depletion of endogenous GPR48 by RNA interference reduced the invasive potential of HeLa and Lewis lung carcinoma cells not only in vitro but also in vivo. Moreover, GPR48 expression was significantly associated with lymph node metastasis and inversely correlated with p27 expression in human colon carcinomas. GPR48 may thus play an important role in invasiveness and metastasis of carcinoma and might therefore represent a potential prognostic marker or therapeutic target.

Animals↗
PubMed2006

Degradation of Tob1 mediated by SCFSkp2-dependent ubiquitination.

Tob1, a member of the Tob/BTG family, is involved in the control of G(1)-S progression by suppressing cyclin D1 expression and acts as a tumor suppressor gene. Tob1 was reported to have a quick turnover through the ubiquitin-proteasome pathway, but proteins involved in this process are still unknown. We showed that Skp2, a substrate-targeting subunit of the SCF (Skp1/Cul1/F-box protein) ubiquitin ligase complex, was involved in ubiquitin-dependent degradation of Tob1. Skp2 interacted with Tob1 and facilitated ubiquitination of Tob1 in intact cells as well as in vitro. Skp2 mutants without the F-box or leucine rich repeat were not able to bind to Tob1 and did not enhance ubiquitination of Tob1. Tob1 was stabilized in both Skp2(-/-) mouse fibroblasts and Skp2 knockdown HeLa cells. Moreover, cyclin D1 expression was suppressed in Skp2 knockdown HeLa cells. These data suggest that Tob1 is a novel target for degradation by the SCF-Skp2 ubiquitin ligase.

Cell Cycle↗
PubMed2006

Immunohistochemical and genetic features of gastric and metastatic liver gastrointestinal stromal tumors: sequential analyses.

Metastatic gastrointestinal stromal tumors (GIST) have an extremely poor prognosis; however, their immunohistochemical and genetic features have not been assessed satisfactorily and the mechanisms responsible for their high malignant potential remain unclear. We examined the immunohistochemical differences between gastric GIST and metastatic lesions in the liver of four patients who had undergone a postgastrectomy hepatectomy for metachronous liver metastases. We also carried out genetic analysis of the tumors in three of the four cases. In all cases, the immunoreactivity profiles, including KIT (CD117), CD34, smooth muscle actin (SMA), desmin, S-100 and vimentin, were similar between the gastric and metastatic tumors, but the Ki67 labeling index in the metastatic GIST was higher than that of the primary GIST. Interestingly, in the case who had received neoadjuvant imatinib therapy before gastrectomy, its therapeutic effect was observed in most of the primary lesion, with the exception of a specific small area with high cellularity. Genetic analysis revealed no acquired mutations in the c-kit or PDGFRA genes in the metastatic lesions in any of the patients, but loss of heterozygosity (LOH) of the c-kit gene was observed mainly in the metastatic tumors in two of the three cases. Furthermore, in the case of neoadjuvant imatinib therapy, LOH of the c-kit gene was shown in the high cellularity area in the primary lesion and metastatic liver GIST. It is suggested that LOH of the c-kit gene is an important event that leads to imatinib resistance and metastatic progression of GIST. In conclusion, both gastric and metastatic GIST had almost the same immunohistochemical features, except for their proliferative activity, and LOH of the c-kit gene played an important role in the process of liver metastasis.

Aged↗
PubMed2006

[Manifestation of liver metastasis 13 years after gastrectomy for gastric GIST].

A 58-year-old Japanese man underwent partial gastrectomy in 1991 for a tumor showing extra-gastric growth measuring 18 x 16.5 x 8.8 cm in size. An immunohistochemical study yielded a diagnosis of gastric GIST with few mitoses. In 2004, abdominal CT showed a solitary liver metastasis without extrahepatic recurrence and right hepatic lobectomy was performed. No adjuvant treatment has been done and he is alive without recurrence 1 year after the hepatectomy. Long term follow-up of more than 10 years is required after resection of primary tumors if they are diagnosed as high risk GISTs with few mitoses.

Gastrectomy↗
PubMed2005

Inhibition of CX3CL1 (fractalkine) improves experimental autoimmune myositis in SJL/J mice.

Idiopathic inflammatory myopathy is a chronic inflammatory muscle disease characterized by mononuclear cell infiltration in the skeletal muscle. The infiltrated inflammatory cells express various cytokines and cytotoxic molecules. Chemokines are thought to contribute to the inflammatory cell migration into the muscle. We induced experimental autoimmune myositis (EAM) in SJL/J mice by immunization with rabbit myosin and CFA. In the affected muscles of EAM mice, CX3CL1 (fractalkine) was expressed on the infiltrated mononuclear cells and endothelial cells, and its corresponding receptor, CX3CR1, was expressed on the infiltrated CD4 and CD8 T cells and macrophages. Treatment of EAM mice with anti-CX3CL1 mAb significantly reduced the histopathological myositis score, the number of necrotic muscle fibers, and infiltration of CD4 and CD8 T cells and macrophages. Furthermore, treatment with anti-CX3CL1 mAb down-regulated the mRNA expression of TNF-alpha, IFN-gamma, and perforin in the muscles. Our results suggest that CX3CL1-CX3CR1 interaction plays an important role in inflammatory cell migration into the muscle tissue of EAM mice. The results also point to the potential therapeutic usefulness of CX3CL1 inhibition and/or blockade of CX3CL1-CX3CR1 interaction in idiopathic inflammatory myopathy.

Animals↗
PubMed2004

Inhibitory effects of bucillamine on the expression of vascular cell adhesion molecule-1 in human umbilical vein endothelial cells.

Bucillamine (BUC) has been found to have beneficial effects in the treatment of rheumatoid arthritis (RA), in which the activation of endothelial cells plays an important role in the pathogenesis. The current studies examined the effect of BUC and its intramolecular disulfide form (BUC-ID) on the expression of adhesion molecules in human umbilical vein endothelial cells (HUVEC) stimulated with tumor necrosis factor-alpha (TNF-alpha). HUVEC (4 x 10(4)/well) were incubated with medium M199 containing heparin and 20% FCS with endothelial cell growth supplement (ECGS) for 24 h in the presence or absence of BUC or BUC-ID, after which the culture medium was replaced with ECGS free medium. Then the cultures were further carried out for additional 24 h with TNF-alpha (10 ng/ml) in the presence or absence of BUC or BUC-ID. BUC-ID, but not BUC, appeared to suppress the expression of VCAM-1 on HUVEC stimulated with TNF-alpha in a dose-response manner at its pharmacologically relevant concentrations (0.3-3.0 microg/ml), whereas only the 3 microg/ml concentration level of BUC-ID had a statistically significant effect, although the effect was relatively small. By contrast, lower concentrations of BUC-ID (1-3 microg/ml) suppressed the secretion of soluble VCAM-1 by HUVEC much more effectively. Of note, at the concentration of 3 microg/ml neither BUC nor BUC-ID significantly influenced the expression of ICAM-1 and E-selectin on TNF-alpha stimulated HUVEC. These results indicate that BUC-ID, but not BUC, specifically downregulates the surface expression of VCAM-1 as well as the release of soluble VCAM-1 by HUVEC stimulated with TNF-alpha. BUC-ID suppressed the production of solubleVCAM-1 by RA bone marrow CD34+ cells stimulated with SCF, GM-CSF and TNF-alpha more effectively than BUC. The data thus suggest that one of the mechanisms of action of BUC involves the inhibition of the activation of endothelial cells.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2004

[A case of gastric GIST treated preoperatively by imatinib mesylate].

Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the human gastrointestinal tract, is thought to originate from the interstitial cells of Cajal. The mutation of c-kit, cording KIT, is essential in the development of GIST. Imatinib mesylate (IM), an agent for chronic myeloid leukemia, was reported to inhibit tyrosine kinase activity of KIT and to be highly effective for GIST. We report, here, a case of huge gastric GIST who underwent neoadjuvant therapy followed by surgical resection. The patient was a 62-year-old man with GIST in cardia (KIT+, CD34+, mitotic rate 5/50 HPF), whose chief complaint was general fatigue. Because the huge tumor, 7.5 cm in size, directly invaded the pancreas, total gastrectomy with distal pancreatosplenectomy was necessary for curative resection. IM was administered (400 mg/body/day) as a neoadjuvant treatment for down-staging of the tumor. Leucopenia (grade 2) and diarrhea (grade 1) were observed as the adverse effects of IM. Partial response was obtained. He underwent proximal gastrectomy without pancreatosplenectomy since CT no longer showed direct invasion to the pancreas. Histological examination of the resected specimen revealed the extensive degeneration of the tumor, in which tumor cells containing condensed nuclei had decreased remarkably. Interestingly, mitotic rate decreased to 0/50 HPF in the effective area of the resected specimen, indicating that recurrent risk might be decreased. A part of the viable tumor cells, however, had the same feature to that in the biopsied specimen before treatment. The results suggest that the heterogeneity of GIST induces different sensitivity to IM. The postoperative course was uneventful and no sign of recurrence was observed 3 months after surgery. Neoadjuvant therapy with IM may become a useful strategy for GIST, as it reduces the tumor size and decreases the recurrence rate.

Antigens, CD34↗
PubMed2004

[Two cases of postoperative recurrence of gastric GIST treated by imatinib].

We report two cases of postoperative recurrence of gastrointestinal stromal tumor (GIST) treated by the tyrosine kinase inhibitor imatinib mesylate (IM), and discuss some important items. Case 1: This 63-year-old Japanese man received a partial gastrectomy for leiomyosarcoma in 1993. Partial hepatectomy and proximal gastrectomy were performed for liver metastasis and local recurrence in 2001. However, 5 months after surgery, a CT scan showed multiple tumors in the liver, lung and thyroid. The patient was treated with 300 mg of IM once daily with transient grade 2 neutropenia and intestinal bleeding. Though the response to treatment was SD-PR initially, a CT scan 15 months after initial treatment demonstrated the regrowth of the tumor in his liver. Case 2: A 63-year-old Japanese woman was treated with 200 mg of IM once daily for multiple liver metastases after gastrectomy for GIST with grade 3 neutropenia and edema of legs. The response to treatment was SD, and continued for 12 months. IM is the treatment of choice for unresectable recurrence of GIST. However, some problems remained. Both basic and clinical research is necessary to increase the therapeutic efficacy of IM.

Antineoplastic Agents↗
PubMed2003

Behçet's disease.

Behçet's disease is characterized by recurrent aphthous stomatitis, uveitis, genital ulcers, and skin lesions. The role of the HLA-B*51 gene has been confirmed in recent years, although its contribution to the overall genetic susceptibility to Behçet's disease was estimated to be only 19%. The production of a variety of cytokines by T cells activated with multiple antigens has been shown to play a pivotal role in the activation of neutrophils. As regards the treatment, anti-tumor necrosis factor alpha therapy has been shown to be effective for mucocutaneous symptoms as well as for sight-threatening panuveitis, although a randomized, controlled trial is required.

Animals↗