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1.
Lab Invest ; 90(3): 496-505, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20065946

ABSTRACT

The Regenerating gene (REG) Ialpha protein, a trophic and/or anti-apoptotic factor, is important in the pathophysiology of gastrointestinal inflammation. Interleukin (IL)-22 is a recently identified cytokine that is suggested to have pivotal roles in inflammatory bowel diseases. We therefore investigated the involvement of the IL-22/REG Ialpha axis and examined the mechanism of regulation of REG Ialpha expression by IL-22 stimulation in ulcerative colitis (UC) mucosa. Expression of IL-22, IL-22 receptor 1 (IL-22R1), and REG Ialpha in UC mucosa was analyzed by real-time RT-PCR and immunohistochemistry. The effects of IL-22 on REG Ialpha protein expression were examined using a small-interfering RNA for STAT3, an MAPK inhibitor or a PI3K inhibitor. The element responsible for IL-22-induced REG Ialpha promoter activation was determined by a promoter deletion and electrophoretic mobility shift assay. The expression of IL-22 was enhanced in infiltrating inflammatory cells, and that of IL-22R1 and REG Ialpha was concurrently enhanced in the inflamed epithelium in UC mucosa. The levels of REG Ialpha and IL-22 mRNA expression were strongly correlated, and the distributions of REG Ialpha- and IL-22R1-positive epithelial cells were very similar. IL-22 simulation enhanced the expression of REG Ialpha protein through STAT3 tyrosine phosphorylation in colon cancer cells. The IL-22-responsive element was located between -142 and -134 in the REG Ialpha promoter region. REG Ialpha protein may have a pathophysiological role as a biological mediator for immune cell-derived IL-22 in the UC mucosa.


Subject(s)
Colitis, Ulcerative/metabolism , Interleukins/metabolism , Lithostathine/metabolism , Adult , Aged , Cell Line, Tumor , Colitis, Ulcerative/physiopathology , Colonic Neoplasms/metabolism , Extracellular Signal-Regulated MAP Kinases/metabolism , Female , Humans , Intestinal Mucosa/metabolism , Lithostathine/genetics , MAP Kinase Signaling System , Male , Middle Aged , Phosphorylation , Promoter Regions, Genetic , Proto-Oncogene Proteins c-akt/metabolism , RNA, Messenger/metabolism , Receptors, Interleukin/metabolism , STAT3 Transcription Factor/metabolism , Young Adult , Interleukin-22
2.
Gastrointest Endosc ; 64(1): 40-4, 2006 Jul.
Article in English | MEDLINE | ID: mdl-16813801

ABSTRACT

BACKGROUND: Magnifying endoscopy is a promising modality for fine observation of minute surface structures and microvessel architecture in gastric lesions. OBJECTIVE: To observe the response of microvessels to epinephrine stimulation in early gastric cancer tissues and to assess the usefulness of magnifying pharmacoendoscopy for histologic diagnosis. DESIGN: This was a prospective pilot study. SETTING: This study was conducted at an academic hospital. PATIENTS: Twenty-nine patients with differentiated early gastric cancer were enrolled. INTERVENTIONS: Microvessels in both the cancerous lesion and its adjacent non-neoplastic gastric mucosa were observed by magnifying endoscopy before and after focal spray with epinephrine solution (0.05 mg/mL). MAIN OUTCOME MEASUREMENTS AND RESULTS: After epinephrine stimulation, noncancerous gastric mucosa surrounding the cancerous lesion showed a change in color from red to white; no microvessels were evident. On the other hand, all the cancerous lesions examined clearly showed enhancement of tumor microvessels. The rate of detection of tumor microvessels by magnifying pharmacoendoscopy (100%) was significantly higher than that by magnifying endoscopy alone (41.3%). LIMITATIONS: This was small pilot study. CONCLUSIONS: Magnifying pharmacoendoscopy with epinephrine is a powerful tool for assessing tumor vascularity and may contribute to the histologic diagnosis of differentiated early gastric cancers before endoscopic treatment.


Subject(s)
Endoscopy, Gastrointestinal/methods , Epinephrine/pharmacology , Microcirculation/drug effects , Stomach Neoplasms/diagnosis , Vasoconstrictor Agents/pharmacology , Aged , Cell Differentiation , Female , Humans , Image Enhancement , Male , Middle Aged , Pilot Projects , Prospective Studies , Stomach Neoplasms/pathology
3.
Biochem Biophys Res Commun ; 328(1): 348-52, 2005 Mar 04.
Article in English | MEDLINE | ID: mdl-15670790

ABSTRACT

We have previously shown that Hes1 is expressed both in putative epithelial stem cells just above Paneth cells and in the crypt base columnar cells between Paneth cells, while Hes1 is completely absent in Paneth cells. This study was undertaken to clarify the role of Hes1 in Paneth cell differentiation, using Hes1-knockout (KO) newborn (P0) mice. Electron microscopy revealed premature appearance of distinct cells containing cytoplasmic granules in the intervillous region in Hes1-KO P0 mice, whereas those cells were absent in wild-type (WT) P0 mice. In Hes1-KO P0 mice, the gene expressions of cryptdins, exclusively present in Paneth cells, were all enhanced compared with WT P0 mice. Immunohistochemistry demonstrated increased number of both lysozyme-positive and cryptdin-4-positive cells in the small intestinal epithelium of Hes1-KO P0 mice as compared to WT P0 mice. Thus, Hes1 appears to have an inhibitory role in Paneth cell differentiation in the small intestine.


Subject(s)
Homeodomain Proteins/metabolism , Intestine, Small/cytology , Intestine, Small/metabolism , Nerve Tissue Proteins/metabolism , Paneth Cells/cytology , Paneth Cells/metabolism , RNA-Binding Proteins/metabolism , alpha-Defensins/metabolism , Animals , Basic Helix-Loop-Helix Transcription Factors , Cell Differentiation/physiology , Mice , Mice, Knockout , Muramidase/metabolism , Protein Precursors/metabolism , Transcription Factor HES-1
4.
Digestion ; 69(3): 177-84, 2004.
Article in English | MEDLINE | ID: mdl-15166487

ABSTRACT

BACKGROUND/AIMS: Although regenerating gene(Reg) I alpha protein has a trophic effect on gastric epithelial cells, it is unclear whether Reg I alpha protein and its receptor are involved in gastric carcinogenesis. Therefore, we investigated the Reg I alpha protein expression in human gastric cancers and assessed its relationship to clinicopathological factors. METHODS: Sixty-one gastric cancer specimens were examined, using immunohistochemistry, for Reg I alpha protein, p53, and proliferating cell nuclear antigen. The expression of both Reg I alpha and Reg receptor mRNA was examined in seven human gastric cancer cell lines (MKN1, MKN28, MKN45, MKN74, KATOIII, GCIY, and AGS) by reverse transcription-polymerase chain reaction and Northern blot analysis. RESULTS: Twenty-three (37.7%) of the 61 gastric cancer tissues samples were positive for Reg I alpha protein. The Reg I alpha expression was significantly related to the presence of lymphatic invasion but not to tumor size, tumor stage, Lauren's classification, presence of venous invasion, lymph node metastases, or p53 overexpression. Gastric cancers positive for Reg I alpha protein showed a significantly higher proliferating cell nuclear antigen labeling index than negative ones. The expression of both Reg I alpha and Reg receptor mRNA was detected in all seven gastric cancer cell lines. CONCLUSION: Reg I alpha protein may play a role in the development of gastric cancers.


Subject(s)
Gene Expression Profiling , Gene Expression Regulation, Neoplastic , Glycoproteins/biosynthesis , Protein Precursors/biosynthesis , Stomach Neoplasms/genetics , Cell Transformation, Neoplastic , Female , Humans , Immunohistochemistry , Lectins, C-Type/biosynthesis , Lithostathine , Male , Middle Aged , Pancreatic Juice , RNA, Messenger/analysis , Reverse Transcriptase Polymerase Chain Reaction , Stomach Neoplasms/physiopathology , Tumor Cells, Cultured
6.
Oncogene ; 23(28): 4921-9, 2004 Jun 17.
Article in English | MEDLINE | ID: mdl-15077160

ABSTRACT

Signal transduction and activator of transcription 3(STAT3) signaling is constitutively activated in various tumors, and is involved in cell survival and proliferation during oncogenesis. There are few reports, however, on the role of STAT3 signaling in gastric cancer. The aim of the present study was to clarify the role of STAT3 signaling in apoptosis and cellular proliferation in gastric cancer. Here we reported that STAT3 was constitutively activated in various human gastric cancer cells and its inhibition by ectopic dominant-negative STAT3 or Janus kinase inhibitor, tyrphostin AG490, induced apoptosis. Furthermore, STAT3 inhibition markedly decreased survivin expression, and forced expression of survivin rescued AGS cells from apoptosis induced by STAT3 inhibition. Although some reports demonstrated that the PI3K/Akt pathway regulates survivin expression, inhibition of the PI3K/Akt pathway did not affect survivin expression in AGS and MKN1 cells. Finally, activated form of STAT3, Tyr-705 phospho-stat3, was found in the nucleus of cancer cells in 11 of 40 (27.5%) human gastric cancer specimens. These findings suggest that constitutively activated STAT3 signaling supports gastric cancer cell survival in association with survivin expression.2004


Subject(s)
Cell Survival/physiology , DNA-Binding Proteins/genetics , Microtubule-Associated Proteins/genetics , Trans-Activators/genetics , Acute-Phase Proteins/genetics , Acute-Phase Proteins/metabolism , Cell Division , Cell Line, Tumor , Cell Nucleus/genetics , DNA-Binding Proteins/metabolism , Gene Expression Regulation, Neoplastic/genetics , Humans , Inhibitor of Apoptosis Proteins , Kinetics , Neoplasm Proteins , STAT3 Transcription Factor , Signal Transduction , Stomach Neoplasms , Survivin , Trans-Activators/metabolism
7.
Biochem Biophys Res Commun ; 312(4): 897-902, 2003 Dec 26.
Article in English | MEDLINE | ID: mdl-14651956

ABSTRACT

Paneth cells, granule-containing cells located at the bottom of the intestinal crypts, have a role in innate mucosal immunity. We identified the exclusive expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) in Paneth cells using single-cell reverse transcription-polymerase chain reaction and cDNA array. Cytosolic total RNA was aspirated from single Paneth cells and other villous epithelial cells (non-Paneth cells) of rats using capillary micropipettes. In addition to lysozyme, secretory phospholipase A2, defensin, TNF-alpha, and xanthine dehydrogenase genes, cDNA array analysis revealed that the GM-CSF gene is specifically present in Paneth cells, whereas GM-CSF receptor beta-chain mRNA is expressed in Paneth cells and other epithelial cells. There was intense immunohistochemical staining of GM-CSF in Paneth cells but not in other epithelial cells. Treatment of IEC6 cells with GM-CSF enhanced expression of CD80 and CD86. Thus, GM-CSF in Paneth cells might have an important role in mucosal immunity through increasing the expression of costimulatory molecules in epithelial cells.


Subject(s)
Gene Expression Regulation/physiology , Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Paneth Cells/metabolism , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/genetics , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/metabolism , Reverse Transcriptase Polymerase Chain Reaction/methods , Animals , Cells, Cultured , Cytoplasm/genetics , Cytoplasm/metabolism , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Intestinal Mucosa/immunology , Intestinal Mucosa/metabolism , Intestine, Small/immunology , Intestine, Small/metabolism , Male , Paneth Cells/immunology , Rats , Rats, Wistar , Receptors, Granulocyte-Macrophage Colony-Stimulating Factor/immunology
8.
Digestion ; 67(1-2): 20-4, 2003.
Article in English | MEDLINE | ID: mdl-12743436

ABSTRACT

BACKGROUND: Cyclooxygenase (COX)-2 is the rate-limiting enzyme in prostaglandin synthesis, and plays an important role in tumor enlargement. COX-2 is expressed in human gastric and colorectal tumors, and the expression increases in a tumor size-dependent manner. In the present study, we attempted to examine the COX-2 expression pattern in gastric hyperplastic polyp, a non-tumorous lesion. PATIENTS AND METHODS: Fifty-eight gastric hyperplastic polyps, obtained by endoscopic polypectomy, were immunostained with anti-COX-2 and antivascular endothelial growth factor (VEGF) antibodies. Microvessel density (MVD) was determined by von Willebrand factor immunostaining. RESULTS: In larger gastric hyperplastic polyps, COX-2 was expressed mainly on the luminal side of the polyp stroma, while it was absent in smaller polyps. A significant correlation between COX-2 immunoreactivity and polyp size was observed (p < 0.01). High VEGF expression and MVD were observed mainly in the same stromal region of the polyps where COX-2 was expressed. Both VEGF expression and MVD were also correlated with polyp size significantly (ps < 0.01). CONCLUSIONS: COX-2 expression increased in a size-dependent manner in non-tumorous hyperplastic polyps, suggesting that COX-2 expression is not necessarily linked to epithelial cell transformation. Moreover, COX-2 may participate in polyp enlargement through angiogenesis by promoting VEGF production.


Subject(s)
Isoenzymes/metabolism , Neovascularization, Pathologic/enzymology , Polyps/blood supply , Polyps/enzymology , Prostaglandin-Endoperoxide Synthases/metabolism , Stomach Neoplasms/blood supply , Stomach Neoplasms/enzymology , Aged , Cyclooxygenase 2 , Female , Gastric Mucosa/blood supply , Gastric Mucosa/enzymology , Gastric Mucosa/pathology , Humans , Hyperplasia/enzymology , Hyperplasia/pathology , Male , Membrane Proteins , Middle Aged , Neovascularization, Pathologic/pathology , Polyps/pathology , Stomach Neoplasms/pathology
9.
FEBS Lett ; 535(1-3): 131-5, 2003 Jan 30.
Article in English | MEDLINE | ID: mdl-12560091

ABSTRACT

Musashi-1, a neural RNA-binding protein, is important for maintaining neural stem cells. Both Musashi-1 and Hes1, a transcriptional factor regulated by Musashi-1, are expressed in the small intestine. Here we show that Musashi-1 is present in a few epithelial cells just above the Paneth cells in the small intestinal crypt, the putative position of stem cells, whereas Hes1 is expressed in lower crypt cells just above the Paneth cells, including Musashi-1-positive cells. Musashi-1 and Hes1 were not expressed in Paneth cells. Notably, Musashi-1 and Hes1 were coexpressed in the crypt base columnar cells located between the Paneth cells. These findings suggest that not only the cells just above Paneth cells but also the crypt base columnar cells between the Paneth cells have stem cell characteristics.


Subject(s)
Homeodomain Proteins/biosynthesis , Intestine, Small/metabolism , Nerve Tissue Proteins/biosynthesis , RNA-Binding Proteins/biosynthesis , Stem Cells/metabolism , Transcription Factors/biosynthesis , Animals , Basic Helix-Loop-Helix Transcription Factors , Biomarkers/analysis , Cell Line , Homeodomain Proteins/genetics , Humans , Intestine, Small/cytology , Intestine, Small/growth & development , Mice , Mice, Inbred ICR , Nerve Tissue Proteins/genetics , Organ Specificity , Paneth Cells/cytology , RNA, Messenger/biosynthesis , RNA-Binding Proteins/genetics , Rats , Stem Cells/cytology , Transcription Factor HES-1 , Transcription Factors/genetics
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