99 research outputs found
BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cancers
BCL6 is a transcriptional repressor that has important functions in lymphocyte differentiation and lymphomagenesis, but there have been no reports of BCL6 expression in gastric cancers. In the present study, we investigated the BCL6 function in gastric cancers. Treatment with TPA resulted in BCL6 degradation and cyclin D2 upregulation. This phenomenon was inhibited by the suppression of the nuclear translocation of HB-EGF-CTF (C-terminal fragment of pro-HB-EGF). The HB-EGF-CTF nuclear translocation leads to the interaction of BCL6 with HB-EGF-CTF and the nuclear export of BCL6, and after that BCL6 degradation was mediated by ubiquitin/proteasome pathway. Real-time RTâPCR and siRNA targeting BCL6 revealed that BCL6 suppresses cyclin D2 expression. Our data indicate that BCL6 interacts with nuclear-translocated HB-EGF-CTF and that the nuclear export and degradation of BCL6 induces cyclin D2 upregulation. We performed immunohistochemical analyses of BCL6, HB-EGF and cyclin D2 in human gastric cancers. The inverse correlation between BCL6 and cyclin D2 was also found in HB-EGF-positive human gastric cancers. BCL6 degradation caused by the HB-EGF-CTF also might induce cyclin D2 expression in human gastric cancers. Inhibition of HB-EGF-CTF nuclear translocation and maintenance of BCL6 function are important for the regulation of gastric cancer progression
Gene expression profile and genomic alterations in colonic tumours induced by 1,2-dimethylhydrazine (DMH) in rats
<p>Abstract</p> <p>Background</p> <p>Azoxymethane (AOM) or 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats shares many phenotypical similarities with human sporadic colon cancer and is a reliable model for identifying chemopreventive agents. Genetic mutations relevant to human colon cancer have been described in this model, but comprehensive gene expression and genomic analysis have not been reported so far. Therefore, we applied genome-wide technologies to study variations in gene expression and genomic alterations in DMH-induced colon cancer in F344 rats.</p> <p>Methods</p> <p>For gene expression analysis, 9 tumours (TUM) and their paired normal mucosa (NM) were hybridized on 4 à 44K Whole rat arrays (Agilent) and selected genes were validated by semi-quantitative RT-PCR. Functional analysis on microarray data was performed by GenMAPP/MappFinder analysis. Array-comparative genomic hybridization (a-CGH) was performed on 10 paired TUM-NM samples hybridized on Rat genome arrays 2 à 105K (Agilent) and the results were analyzed by CGH Analytics (Agilent).</p> <p>Results</p> <p>Microarray gene expression analysis showed that <it>Defcr4</it>, <it>Igfbp5</it>, <it>Mmp7, Nos2, S100A8 </it>and <it>S100A9 </it>were among the most up-regulated genes in tumours (Fold Change (FC) compared with NM: 183, 48, 39, 38, 36 and 32, respectively), while <it>Slc26a3</it>, <it>Mptx</it>, <it>Retlna </it>and <it>Muc2 </it>were strongly down-regulated (FC: -500; -376, -167, -79, respectively). Functional analysis showed that pathways controlling cell cycle, protein synthesis, matrix metalloproteinases, TNFα/NFkB, and inflammatory responses were up-regulated in tumours, while Krebs cycle, the electron transport chain, and fatty acid beta oxidation were down-regulated. a-CGH analysis showed that four TUM out of ten had one or two chromosomal aberrations. Importantly, one sample showed a deletion on chromosome 18 including <it>Apc</it>.</p> <p>Conclusion</p> <p>The results showed complex gene expression alterations in adenocarcinomas encompassing many altered pathways. While a-CGH analysis showed a low degree of genomic imbalance, it is interesting to note that one of the alterations concerned <it>Apc</it>, a key gene in colorectal carcinogenesis. The fact that many of the molecular alterations described in this study are documented in human colon tumours confirms the relevance of DMH-induced cancers as a powerful tool for the study of colon carcinogenesis and chemoprevention.</p
Expression of CDX2 and Hepatocyte Antigen in Benign and Malignant Lesions of Gallbladder and Its Correlation with Histopathologic Type and Clinical Outcome
Recent studies have shown that both CDX2 and Hepatocyte antigen (Hep) are detected in different types of cancer and associated with clinical prognosis. However, fever studies have examined gallbladder cancer specimens, and little is known about the clinicopathological significance of both CDX2 and Hep expression in gallbladder adenocarcinomas. In present study, we examined the expression frequencies of CDX2 and Hepatocyte antigen (Hep), and explored their clinicopathologic significances in gallbladder adenocarcinoma. Immunohistochemistry was used to detect and compare the frequencies of CDX2 and Hep expression in 108 samples of gallbladder adenocarcinoma, 46 peri-tumor tissues and 35 chronic cholecystitis. The expression frequencies for CDX2 and Hep were 49/108 (45.4%) and 45/108 (41.7%) in gallbladder carcinoma; 13/46 (28.3%) and 11/46 (23.9) in peri-tumor tissues; 5/35 (14.3%) and 2/35 (5.7%) in chronic cholecystitis. The positive staining of CDX2 or Hep in gallbladder adenocarcinoma was significantly higher than that in peritumoral tissues (both, Pâ<â0.05), and chronic cholecystits (both, Pâ<â0.01). The expression of CDX2 or Hep was negatively correlated to grade of differentiation, tumor size and lymph node metastasis (Pâ<â0.01 or Pâ<â0.05). Elevated expression frequency of CDX2 or Hep was associated with increased overall survival (Pâ=â0.003 or Pâ=â0.002). Multivariate Cox regression analysis showed that CDX2 (Pâ=â0.014) or Hep (Pâ=â0.026) expression was an independent prognostic predictor in gallbladder adenocarcinoma. CDX2 and Hep might function as important biological markers in the development and prognosis of gallbladder adenocarcinoma
Managing refractory Crohn's disease: challenges and solutions
Satoshi Tanida, Keiji Ozeki, Tsutomu Mizoshita, Hironobu Tsukamoto, Takahito Katano, Hiromi Kataoka, Takeshi Kamiya, Takashi Joh Department of Gastroenterology and Metabolism, Nagoya City University Graduate School of Medical Sciences, Aichi Prefecture, Japan Abstract: The goals of treatment for active Crohn's disease (CD) are to achieve clinical remission and improve quality of life. Conventional therapeutics for moderate-to-severe CD include 5-aminosalicylic acid, corticosteroids, purine analogs, azathioprine, and 6-mercaptopurine. Patients who fail to respond to conventional therapy are treated with tumor necrosis factor (TNF)-α inhibitors such as infliximab and adalimumab, but their efficacy is limited due to primary nonresponse or loss of response. It is suggested that this requires switch to another TNF-α inhibitor, a combination therapy with TNF-α blockade plus azathioprine, or granulocyte and monocyte adsorptive apheresis, and that other therapeutic options having different mechanisms of action, such as blockade of inflammatory cytokines or adhesion molecules, are needed. Natalizumab and vedolizumab are neutralizing antibodies directed against integrin a4 and a4ß7, respectively. Ustekinumab is a neutralizing antibody directed against the receptors for interleukin-12 and interleukin-23. Here, we provide an overview of therapeutic treatments that are effective and currently available for CD patients, as well as some that likely will be available in the near future. We also discuss the advantages of managing patients with refractory CD using a combination of TNF-α inhibitors plus azathioprine or intensive monocyte adsorptive apheresis. Keywords: adalimumab, granulocyte and monocyte adsorptive apheresis, combination therapy, complete remissio
Loss of MUC2 expression correlates with progression along the adenoma-carcinoma sequence pathway as well as de novo carcinogenesis in the colon
Aims: We have previously demonstrated
links between clinicopathological findings and
phenotypes using several gastric and intestinal
phenotypic markers in stomach and pancreatic cancers.
However, the clinicopathological significance of the
phenotype and Cdx2 expression has hitherto remained
unclear in colorectal carcinogenesis. Methods and
results: We examined the correlation between gastric and
intestinal phenotypic expression in 91 primary early
carcinomas of the colon. MUC2 expression
demonstrated a significant decrease from tubular/
tubulovillous adenomas with moderate atypia, through
intramucosal carcinomas, to cancers with submucosal
invasion (P<0.0001). Intramucosal de novo carcinomas
(flat type carcinomas without adenomatous components)
exhibited a greater decrease of MUC2 than intramucosal
lesions with adenomatous components. Expression of
MUC5AC also decreased significantly with progression
according to the tubular/tubulovillous adenomacarcinoma
sequence, carcinomas with villous
adenomatous components having a higher level
compared with their tubular adenomatous counterparts,
suggesting differences in the pathway of malignant
transformation. Cdx2 nuclear expression was maintained
in all of the adenomas and early carcinomas examined.
Conclusions: Our data suggest that the reduction of
MUC2 expression may be associated with the occurrence and progression of colorectal carcinomas in
both adenoma-carcinoma sequence pathway and de novo
carcinogenesis. Tumor-suppressive effects of Cdx2 may
be preserved during early stages of colorectal
carcinogenesis
Synergistic upregulation of inducible nitric oxide synthase and cyclooxygenase-2 in gastric mucosa of Mongolian gerbils by a high-salt diet and Helicobacter pylori infection
Aims: The intake of salt and salty food is
known as a risk factor for gastric cancer. We have
previously demonstrated that a high-salt diet dosedependently
enhances Helicobacter pylori (H. pylori)-
associated gastritis and stomach carcinogenesis in
Mongolian gerbils. In this study, we focused on the
influence of excessive salt intake on the expression of
inflammatory mediators involved in progression of H.
pylori-induced chronic gastritis.
Methods and Results: A total of 45 stomach samples
from Mongolian gerbils were evaluated by
immunohistochemistry. The animals were infected with
H. pylori and fed basal (0.32%) or a high-salt (10%)
diet, and sacrificed after 40 weeks. Proliferative activity
and expression of cyclooxygenase-2 (COX-2) in gastric
mucosa were significantly increased in H. pyloriinfected
gerbils. The additional high-salt diet
significantly up-regulated the expression of inducible
nitric oxide synthase (iNOS) and COX-2 in H. pyloriinfected
groups (P<0.01 and P<0.05, respectively), while
no significant effects were noted in non-infected
animals. There was significant synergistic interaction
between H. pylori infection and 10% NaCl diet on the expression of iNOS (P<0.05) and also a tendency for
enhanced COX-2 expression (P=0.0599).
Conclusions: The present results suggest that a high-salt
diet works synergistically with H. pylori infection to
enhance iNOS and COX-2 expression in the gastric
mucosa of Mongolian gerbils, and support the
hypothesis that excessive salt intake may be associated
with progression of H. pylori-induced gastritis
Characterization of 42 highly polymorphic bovine microsatellite markers
We have isolated 42 highly polymorphic microsatellite (GT/CA)(n) markersfrom Japanese black cattle Wagyu (Bos taurus). Forty-one of the markers wereassigned to bovine autosomes with lod scores >6, through linkage analysesperformed on the international Bovine Reference Family Panel (IBRP). Theremaining marker showed X-linked inheritance. These markers exhibited anaverage heterozygosity value of 0.67 with between four and 17 alleles on theIBRP
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