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Yunyan Wu, Fuyuki Sato,
Toshiyuki Yamada,
Ujjal Kumar Bhawal,
Takeshi Kawamoto,
Katsumi Fujimoto,
Mitsuhide Noshiro,
Hiroko Seino,
Satoko Morohashi,
Kenichi Hakamada,
Yoshimitsu Abiko,
Yukio Kato,
Hiroshi Kijima
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ABSTRACT: DEC1 (BHLHE40/Stra13/Sharp2) is a basic helix-loop-helix (bHLH) transcription factor that is involved in the regulation of apoptosis and cell proliferation and the response to hypoxia. Epithelial-mesenchymal transition (EMT) is an important step leading to invasion and migration of various tumor cells, and TGF-β treatment has been shown to induce cancer cells to undergo EMT. However, the significance of DEC1 in TGF-β-induced EMT remains unknown. We examined the role of DEC1 in EMT of PANC-1 cells, a human pancreatic cancer cell line. As a result, we found that DEC1 was upregulated by TGF-β in PANC-1 cells, and regulated the expression and the levels of nuclear, cytoplasmic or membrane localization of EMT-related factors, including phosphorylated Smad3 (pSmad3), snail, claudin-4 and N-cadherin. In the presence of TGF-β, DEC1 knockdown by siRNA inhibited morphological changes during EMT processes, while TGF-β induced PANC-1 cells to taken on a spindle-shaped morphology. Furthermore, a combination treatment of DEC1 expression with TGF-β was closely linked to the migration and invasion of PANC-1 cells. Immunohistochemically, DEC1 and pSmad3 were detected within pancreatic cancer tissues, whereas claudin-4 expression was weaker in the cancer tissues compared with the adjacent non-cancer pancreatic tissues. These findings suggest that DEC1 plays an important role in the regulation of these EMT-related factors in pancreatic cancer.
International Journal of Oncology 07/2012; · 2.40 Impact Factor
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Fuyuki Sato,
Haruka Kawamura,
Yunyan Wu,
Hiroyasu Sato,
Daiki Jin,
Ujjal Kumar Bhawal,
Takeshi Kawamoto,
Katsumi Fujimoto,
Mitsuhide Noshiro,
Hiroko Seino,
Satomo Morohashi,
Yukio Kato,
Hiroshi Kijima
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ABSTRACT: The basic helix loop helix (bHLH) transcription factor DEC2 is associated with the regulation of apoptosis, circadian rhythm and the response to hypoxia. However, the significance of DEC2 in pancreatic cancer remains unknown. Here, we showed for the first time that DEC2 inhibits the progression of human pancreatic cancer. Human pancreatic cancer BxPC-3 cells were treated with or without transforming growth factor-β (TGF-β), siRNA against DEC2, or a combination of TGF-β and DEC2 siRNA or DEC2 overexpression. The cells were analyzed by RT-PCR, real-time PCR, western blotting, immunofluorescent staining and ChIP assay. We also performed immunohistochemical analyses of DEC2 expression in surgically-resected pancreatic cancers. The expression of DEC2 was increased in TGF-β-treated BxPC-3 cells. In the presence of TGF-β, DEC2 overexpression decreased the migration and invasion of BxPC-3 cells. Knockdown of DEC2 by siRNA in the presence of TGF-β significantly increased the expression and nuclear concentration of slug. We also showed that DEC2 siRNA decreased the binding of DEC2 to the E-box of the slug promoter. Immunohistochemically, little DEC2 was detected in pancreatic cancer tissues, whereas significant amounts were detected in the adjacent non-cancerous pancreatic tissues. These results indicate that DEC2 has inhibitory effects against human pancreatic cancer that involve TGF-β and slug.
International Journal of Molecular Medicine 06/2012; 30(3):495-501. · 1.98 Impact Factor
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Ujjal K Bhawal,
Yumi Ito,
Keiji Tanimoto, Fuyuki Sato,
Katsumi Fujimoto,
Takeshi Kawamoto,
Tomonori Sasahira,
Nobushiro Hamada,
Hiroki Kuniyasu,
Hirohisa Arakawa,
Yukio Kato,
Yoshimitsu Abiko
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ABSTRACT: Growing evidence indicates that inflammation is a contributing factor leading to cancer development. However, pathways involved in this progression are not well understood. The involvement of DEC1 in cancer prompted us to examine whether pro-inflammatory cytokine interleukin-1β (IL-1β) induces the expression of DEC1 in oral inflammation. We found that IL-1β up-regulated DEC1 and hypoxia-inducible factor-1α (HIF-1α) protein and elevated the HIF-1α-responsive gene vascular endothelial growth factor (VEGF) expression in human primary gingival cells. HIF-1α and DEC1 immunoreactivity were significantly higher in the cases of gingival inflammation. We demonstrate that IL-1β up-regulates DEC1 and HIF-1α protein through a classical inflammatory signaling pathway involving Akt. Our data strongly suggest that PI-3K-Akt is an upstream participant in IL-1β-mediated DEC1 and HIF-1α induction. This is supported by the following data: (1) IL-1β induces 473 serine phosphorylation of Akt; (2) IL-1β-mediated Akt activation occurs in a PI-3K-dependent manner, and specific inhibition of PI-3K prevents Akt phosphorylation; and (3) inhibition of Akt prevents IL-1β-mediated DEC1 and HIF-1α induction. Taken together, these results suggest that DEC1 is one of the important transcription factors in inflammation.
Journal of Cellular Biochemistry 05/2012; 113(10):3246-53. · 2.87 Impact Factor
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Fuyuki Sato,
Hiroyasu Sato,
Daiki Jin,
Ujjal Kumar Bhawal,
Yunyan Wu,
Mitsuhide Noshiro,
Takeshi Kawamoto,
Katsumi Fujimoto,
Hiroko Seino,
Satoko Morohashi,
Yukio Kato,
Hiroshi Kijima
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ABSTRACT: Smads are intracellular signaling mediators. Complexes of Smad2 and Smad3 with Smad4 transmit transforming growth factor-beta (TGF-β) receptor-induced signaling. Snail plays important roles in mesoderm formation, gastrulation, neural crest development, and epithelial mesenchymal transition. However, it remains unknown whether Smad3 and Snail expression is circadian rhythm-dependent. Here, we showed for the first time that Smad3 and Snail show circadian expression in human gingival fibroblasts (HGF-1) and human mesenchymal stem cells (MSC) after serum shock. They also showed circadian expression in the mouse liver. We confirmed that BMAL1/2, DEC1/2, VEGF, and PER1/2/3 also show circadian expression in both HGF-1 and MSC. The mRNA peaks and phases in circadian expression of these genes differed between HGF-1 and MSC. In a luciferase assay, Smad3 promoter activity was upregulated by CLOCK/BMAL1. These findings suggest that Smad3 and Snail have circadian rhythm in vitro and vivo, and that circadian expression of Smad3 depends on CLOCK/BMAL1.
Biochemical and Biophysical Research Communications 02/2012; 419(2):441-6. · 2.48 Impact Factor
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ABSTRACT: DEC1 (BHLHE40/Stra13/Sharp2) and DEC2 (BHLHE41/Sharp1) are basic helix-loop-helix (bHLH) transcription factors that are involved in the regulation of apoptosis, cell proliferation, circadian rhythms and the response to hypoxia. We previously showed the functional effects of DEC1 and DEC2 on apoptosis in human breast cancer MCF-7 cells. However, the roles of DEC1 and DEC2 in oral cancer are poorly understood. We examined whether DEC1 and DEC2 are involved in the regulation of apoptosis in human oral cancer HSC-3 and CA9-22 cells. The expression of DEC2 was upregulated by cis-diamminedichloroplatinum (II) (cisplatin: CDDP) treatment in HSC-3 cells, whereas CDDP treatment had little effects on the expression of DEC2 in CA9-22 cells. We showed that DEC2 overexpression inhibits pro-apoptotic factor Bim and inhibits apoptosis induced by CDDP in HSC-3 cells, whereas it had little effects on apoptosis in CA9-22 cells. DEC1 overexpression had little effects on apoptosis induced by CDDP in these cells. We also found that CDDP upregulated the amounts of DEC2 in the nucleus in HSC-3 cells. These results suggest that DEC2 has anti-apoptotic effects on apoptosis induced by CDDP in HSC-3 cells.
Biomedical Research 01/2012; 33(2):75-82. · 1.15 Impact Factor
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ABSTRACT: Interferon (IFN)-stimulated gene 20 (ISG20) is a 3'-to-5' exonuclease specific for single-stranded RNA and involved in host defense reactions against RNA viruses. The expression and the role of ISG20 in mesangial cells have not been reported.
Normal human mesangial cells were cultured and treated with polyinosinic-polycytidylic acid (poly (I:C)), an authentic double-stranded RNA which mimics viral infection to cells. The effect of RNA interference of Toll-like receptor 3 (TLR3) or IFN-β on the ISG20 expression was examined. The effect of a blocking antibody against the receptor for IFN-β or anti-inflammatory steroid dexamethasone was also examined.
Treatment of cells with poly (I:C) induced the expression of ISG20. The poly (I:C)-induced expression of ISG20 was inhibited by knockdown of TLR3, IFN regulatery factor 3 (IRF3) or IFN-β. Blocking of the receptor for IFN-β suppressed and overexpression of IFN-β enhanced ISG20 expression. The poly (I:C)-induced expressions of IFN-β and ISG20 were inhibited by dexamethasone. Transfection of mesangial cells with poly (I:C) or 5'-triphosphate single-stranded RNA as a complex with cationic lipid also induced the expression of ISG20, and this was inhibited by knockdown of retinoic acid-inducible gene-I (RIG-I).
Poly (I:C) induces the expression of ISG20 in mesangial cells. ISG20 may be involved in anti-viral reactions in renal mesangial cells. TLR3, IRF3 and de novo synthesized IFN-β may mediate the poly (I:C)-induced expression of ISG20, and RIG-I may mediate ISG20 expression induced by poly (I:C)/cationic lipid complex.
Nephron Experimental Nephrology 08/2011; 119(2):e40-8. · 1.86 Impact Factor
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Ujjal K Bhawal, Fuyuki Sato,
Yuki Arakawa,
Katsumi Fujimoto,
Takeshi Kawamoto,
Keiji Tanimoto,
Yumi Ito,
Tomonori Sasahira,
Takashi Sakurai,
Masaru Kobayashi,
Isamu Kashima,
Hiroshi Kijima,
Hiroki Kuniyasu,
Yoshimitsu Abiko,
Yukio Kato,
Sadao Sato
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ABSTRACT: DEC1 (also known as Stra13/Bhlhb2/Sharp2) and DEC2 (also known as Bhlhb3/Sharp1) are two paralogous basic helix-loop-helix (bHLH) transcriptional regulators which exhibit a robust circadian gene expression pattern in the suprachiasmatic nucleus (SCN) and in peripheral organs. DEC1 has been suggested to play key roles in mammalian cell differentiation, the cell cycle and circadian regulation, hypoxia response, and carcinogenesis. Here we show that DEC1 overexpression exhibits delayed wound healing and reduces cell proliferation, migration, and invasion. DEC1 strongly repressed the promoter activity of cyclin D1. We further identify a possible DEC-response element in the cyclin D1 promoter region, and confirmed the direct binding of DEC1 to that element. Forced expression of DEC1 efficiently repressed the cyclin D1 promoter and expression. Our clinical data provide the first evidence that there is a strong inverse correlation between DEC1 and cyclin D1 expression in oral cancer, and DEC1 expression significantly correlated with clinicopathological parameters. We suggest that radiation-induced DEC1 overexpression and Akt phosphorylation in cancer cells are mediated via PI-3K signalling. Overexpression of DEC1 activates the PI-3K/Akt signalling pathway through reactive oxygen species (ROS).
The Journal of Pathology 07/2011; 224(3):420-9. · 6.32 Impact Factor
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ABSTRACT: PERIOD (PER) proteins are transcriptional regulators that are involved in circadian rhythms, sleep homeostasis, cell proliferation and tumour progression. We previously showed that the expression of PER1 was related to the regulation of apoptosis in human pancreatic cancer and hepatocellular carcinoma cells. However, the significance of PER in oral cancer has not been reported, and the detailed molecular mechanisms by which anti-tumour drug induces apoptosis in gingival cancer cells are not well understood. We examined whether PER1 and PER3 are involved in the regulation of apoptosis in human gingival cancer CA9-22 cells. The expression of PER1 and PER3 was upregulated and downregulated, respectively, by cis-diamminedichloroplatinum (II) (cisplatin: CDDP) treatment in CA9-22 cells, whereas CDDP treatment had little effects on the expression of PER1 and PER3 in human gingival fibroblasts (HGF-1). We found that short interference RNA (siRNA)-mediated knockdown of PER1 enhanced apoptosis of CA9-22 cells, and that PER1 regulated the amount of Bim, an apoptosis-related molecule. On the other hand, PER3 knockdown had an inhibitory effect on the apoptosis of CA9-22 cells induced by CDDP treatment. These results suggest that the alternation of expression of PER1 and PER3 was related to the apoptosis of CA9-22 cells. Furthermore, PER1 was intensely stained in the gingival cancer tissues, whereas PER3 was significantly stained in the non-tumour tissues by immunohistochemistry. These findings suggest that PER1 and PER3 have anti-apoptotic and pro-apoptotic effects in human gingival cancer CA9-22 cells, respectively. The balance of PER1 and PER3 may modulate apoptotic reactions in gingival cancer cells.
European journal of cancer (Oxford, England: 1990) 04/2011; 47(11):1747-58. · 4.12 Impact Factor
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ABSTRACT: Differentiated embryonic chondrocyte gene (DEC) 1 (BHLHE40/Stra13/Sharp2) and DEC2 (BHLHE41/Sharp1) are basic helix-loop-helix (bHLH) transcription factors that are associated with the regulation of apoptosis, cell proliferation and circadian rhythms, as well as malignancy in various cancers. However, the roles of DEC1 and DEC2 expression in breast cancer are poorly understood. In this study, we sought to examine the roles of DEC1 and DEC2 in MCF-7 human breast cancer cells that had been treated with paclitaxel. The expression of DEC1 and DEC2 was up-regulated in paclitaxel-treated MCF-7 cells. Knockdown of DEC1 by siRNA decreased the amount of cleaved poly (ADP-ribose) polymerase (PARP), after treatment with paclitaxel, whereas DEC2 knockdown increased the amount of cleaved PARP in both the presence and absence of paclitaxel. Immunofluorescent staining revealed that paclitaxel treatment increased the amount of DEC1 in the nucleus, and increased the amount of DEC2 in both the nucleus and cytoplasm. These results indicate that DEC1 has pro-apoptotic effects, whereas DEC2 has anti-apoptotic effects on the paclitaxel-induced apoptosis in human breast cancer MCF-7 cells.
International Journal of Molecular Medicine 02/2011; 27(4):491-5. · 1.98 Impact Factor
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ABSTRACT: Recent advances in endoscopic submucosal dissection (ESD) techniques contribute to endoscopic treatment of early gastric cancer (EGC). Recognition of chronic atrophic gastritis as the background is important for high-quality detection and diagnosis of EGC. But, relationships between EGC and atrophy of the background gastric mucosa caused by Helicobacter pylori are not well understood. The present study demonstrated histopathological phenotypes of EGC, as well as chronic atrophic gastritis as background mucosa of EGC. We evaluated mucosal heights, number of glands, and degree of intestinal metaplasia (IM) of the background gastric mucosa, using 81 cases of EGC resected by ESD. Gastric phenotype cancer cases showed IM of the background gastric mucosa less frequently, compared with intestinal phenotype cancer cases (score of IM, 1.15 vs. 1.65, P = 0.012). The average mucosal heights around EGC were lower in moderately to poorly differentiated adenocarcinoma cases than well differentiated adenocarcinoma cases (442.6 µm vs. 500.2 µm, P = 0.011). The mucosal atrophy indicated by average heights of background mucosa was low in the gastric phenotype cancer cases, compared with the intestinal phenotype cancercases (452.8 µm vs. 505.6 µm, P = 0.018). In the fundic gland area, the mucosal heights were low in the gastric phenotype cancer cases, compared with the intestinal phenotype cancer cases (413.2 µm vs. 495.5 µm, P = 0.015). Our results using EGC specimens indicated that gastric phenotype cancer and moderately to poorly differentiated adenocarcinoma had atrophic background mucosa with lower mucosal heights and less IM. The atrophic gastric mucosa with less IM is thought to play an important role in gastric carcinogenesis, especially tumoriogenesis of gastricphenotype cancer.
Biomedical Research 01/2011; 32(2):127-34. · 1.15 Impact Factor
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ABSTRACT: Differentiated embryo-chondrocyte 2 (DEC2), a basic-helix-loop-helix transcriptional factor, is involved in various biological reactions by regulating the expression of its target genes. In the present study, we demonstrated DEC2 expression in response to the treatment with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, in cultured human mesangial cells. RNA interference against DEC2 enhanced the poly IC-induced expression of IFN-β and its downstream genes, retinoic acid-inducible gene-I (RIG-I) and CCL5. Knockdown of TLR3 abolished the poly IC-induced DEC2 expression. DEC2 expression may constitute a negative feedback system for the IFN-β/RIG-I/CCL5 pathway in the glomerulus, which may play a role in controlling protracted inflammatory reactions in the kidney.
Immunology letters 12/2010; 136(1):37-43. · 2.91 Impact Factor
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ABSTRACT: ABSTRACT: BACKGROUND: Claudin-1 is a membrane protein of tight junctions, and is associated with the development of various cancers. However, the significance of claudin-1 expression in cancer cells is not well understood. Here, we showed for the first time the anti-apoptotic effect of claudin-1 in human breast cancer MCF-7 cells. METHODS: Human breast cancer MCF-7 and T47D cells were treated with or without tamoxifen, siRNA against claudin-1, or tamoxifen and claudin-1 siRNA. The samples were analyzed by RT-PCR, Western blotting or immunofluorescent staining. RESULTS: The expression of claudin-1 was upregulated in tamoxifen-treated MCF-7 cells, whereas the expression of claudin-1 was not altered in tamoxifen-treated T47D cells. Knockdown of claudin-1 by siRNA increased the amount of poly (ADP-ribose) polymerase (PARP) regardless of tamoxifen treatment in MCF-7 cells, but not T47D cells. In the cell membranes of the MCF-7 cells, tamoxifen treatment increased the amount of claudin-1, but decreased the amount of beta-catenin. Claudin-1 siRNA increased the amount of E-cadherin in the cytoplasm of the MCF-7 cells as well as the amount of beta-catenin in their cell membranes. CONCLUSION: These results indicate that claudin-1 has anti-apoptotic effects, and is involved in the regulation of the expression and subcellular localization of beta-catenin and E-cadherin in MCF-7, but not T47D cells.
BMC Cancer 10/2010; 10(1):548. · 3.01 Impact Factor
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ABSTRACT: Proteoglycans (PGs) are complex glycohydrates which are widely distributed in extracellular matrix (ECM). PGs are involved in the construction of ECM, cell proliferation and differentiation. ECM components are involved in transduction of proinflammatory responses, but it is still unknown whether PGs are involved in inflammatory response. In this study, we investigated the effect of PG extracted from salmon cartilage on the progression of experimental colitis-induced in severe combined immunodeficiency mice by cell transfer from interleukin-10 (IL-10)-/- mice. IL-10-/- cell-transferred mice showed weight loss, colon shortening and histological appearance of mild colitis. Daily oral administration of PG attenuated the clinical progression of colitis in a dose-dependent manner. Colitis-induced mice showed the elevated expression of IFN-γ, IL-12, TNF-α, IL-21, IL-23p19, IL-6, IL-17A and retinoic acid-related orphan receptor γt (RORγt) in lamina propria mononuclear cells (LPMCs) and oral administration of PG suppressed the expression of these factors. Conversely, expression of Foxp3 that induces CD4+CD25+ regulatory T cells in LPMCs was enhanced by PG administration. These findings suggested that salmon PG attenuated the progression of colitis due to suppression of inflammatory response by enhancement of regulatory T cell induction.
Biochemical and Biophysical Research Communications 10/2010; 402(2):209-15. · 2.48 Impact Factor
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Yang Liu, Fuyuki Sato,
Takeshi Kawamoto,
Katsumi Fujimoto,
Satoko Morohashi,
Harue Akasaka,
Jun Kondo,
Yunyan Wu,
Mitsuhide Noshiro,
Yukio Kato,
Hiroshi Kijima
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ABSTRACT: DEC1 (BHLHB2/Stra13/Sharp2) and DEC2 (BHLHB3/Sharp1) are basic helix-loop-helix (bHLH) transcription factors that are involved in circadian rhythms, differentiation and the responses to hypoxia. We examined whether DEC1 and DEC2 are involved in apoptosis regulation, in human breast cancer MCF-7 cells. We found that siRNA-mediated knockdown of DEC2 resulted in marked enhancement of apoptosis compared with that in control cells transfected with nonspecific siRNA. However, knockdown of DEC1 by siRNA did not affect cell survival. Knockdown of DEC2 affected the expression of mRNA or proteins related to apoptosis, such as Fas, c-Myc, caspase-8, poly (ADP-ribose) polymerase (PARP) and Bax. We also showed that tumor necrosis factor-alpha (TNF-alpha) up-regulates the expression of DEC1 and DEC2. DEC2 over-expression caused by the transfection of an expression vector reduced the amounts of cleaved PARP and caspase-8 induced by TNF-alpha treatment, whereas DEC1 over-expression increased it. Finally, we revealed that treatment with double knockdown against both DEC1 and DEC2 decreased the amounts of cleaved PARP and caspase-8 induced by DEC2 siRNA with or without TNF-alpha. These data indicate that DEC2 has an anti-apoptotic effect, whereas DEC1 has a pro-apoptotic effect, which are involved in the balance of survival of human breast cancer MCF-7 cells.
Genes to Cells 03/2010; 15(4):315-25. · 2.68 Impact Factor
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Hiroyuki Jin,
Satoko Morohashi, Fuyuki Sato,
Yasuyuki Kudo,
Harue Akasaka,
Shinji Tsutsumi,
Hiroshi Ogasawara,
Keiichi Miyamoto,
Naoki Wajima,
Hitoshi Kawasaki,
Kenichi Hakamada,
Hiroshi Kijima
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ABSTRACT: Esophageal squamous cell carcinoma (ESCC) has been generally considered as one of the most aggressive cancers with poor prognosis. Vimentin is the major protein constituent of intermediate filaments in normal and neoplastic mesenchymal cells, and has been regarded as a marker of epithelial-mesenchymal transition (EMT). However, little is known about ESCC with vimentin expression as a marker of EMT. In this study, we analyzed vimentin expression in 129 cases of ESCC in order to elucidate whether vimentin expression is correlated with clinicopathological features and aggressive behavior of ESCC. Vimentin expression was identified in 96 of the 129 cases (74.4%). The cases with vimentin-positive carcinoma cells showed a significantly higher incidence of lymph node metastasis (P = 0.001). Carcinomas with vimentin expression were more advanced in terms of tumor status and lymphatic invasion (P = 0.001, P = 0.009, respectively), and associated with stronger stromal alpha-smooth muscle actin (alpha-SMA) expression (P < 0.001). Vimentin expression was also associated with distant metastasis, including distant node metastasis (P = 0.014). Vimentin expression in both primary and metastatic carcinomas was found in 68.6% (48/70) of the cases, while no vimentin expression in both primary and metastatic carcinomas comprised 92.3% of the cases (12/13) (P < 0.001). In conclusion, we demonstrated that vimentin expression in ESCC is an independent predictor of lymph node metastasis (multivariate analysis, P = 0.014, odds ratio: 3.314, 95% confidence interval: 1.276-8.605). In addition, vimentin expression was frequently retained in metastatic carcinoma of the lymph node.
Biomedical Research 01/2010; 31(2):105-12. · 1.15 Impact Factor
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ABSTRACT: PERIOD1 (PER1) is a clock gene. We examined the effect of knockdown of PER1 on apoptosis in pancreatic cancer (MIA PaCa-2 and PANC-1) and hepatocellular carcinoma (HepG2) cells. Transfection of siRNA against PER1 into these cells increased the cleaved forms of caspases and poly-ADP-ribose-polymerase and induced apoptosis in all three cell lines. In the two pancreatic cancer cell lines, PER1 knockdown resulted in upregulation of Bax and downregulation of Bcl-2. Expression of p53 was not altered in the two pancreatic cancer cell lines containing mutated p53, but was upregulated in the HepG2 cells containing wild-type p53. Cell proliferation of MIA PaCa-2 and HepG2 was inhibited by PER1 knockdown. We also examined, by immunohistochemical staining, the expression of PER1 in pancreatic cancer tissue and found that PER1 was strongly expressed in pancreatic cancer cells. These results indicate that PER1 acts as an anti-apoptotic factor in pancreatic cancer cells.
Journal of biochemistry 09/2009; 146(6):833-8. · 1.95 Impact Factor
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ABSTRACT: Extrahepatic bile duct carcinoma is one of the most extremely aggressive cancers with poor prognosis after curative resection. Syndecan-1 and E-cadherin are transmembrane glycoproteins, and have important roles in cell-cell adhesion and tumor progression. In this study, we examined 84 surgically resected cases of extrahepatic bile duct adenocarcinoma to clarify clinicopathological significance of syndecan-1/E-cadherin expression. Reduced expressions of syndecan-1 and Ecadherin were found in 69.0% (58/84) and 46.4% (39/84) of the bile duct carcinomas. Reduced syndecan-1 expression was correlated with lymphatic/venous/nervous invasion (P < 0.0001), and was associated with short overall survival (P = 0.0002). Reduced E-cadherin expression was correlated with lymphatic and nervous invasion (P = 0.008, P < 0.0001, respectively), and was associated with short overall survival (P = 0.0038). The results indicated that reduced syndecan-1/E-cadherin expression may be good indicators of recurrence and prognosis in extrahepatic bile duct carcinoma.
Biomedical Research 04/2009; 30(2):79-86. · 1.15 Impact Factor
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ABSTRACT: Following hormone therapy, residual carcinoma is frequently difficult to identify on HE-stained prostatectomy specimens. The aim of the present study was therefore to investigate whole-mounted specimens obtained by radical prostatectomy from patients who had undergone hormone therapy. Formalin-fixed and paraffin-embedded specimens were immunostained with prostate secretory cell markers including prostate-specific antigen (PSA), P504S (alpha-methylacyl-coenzyme A racemase, AMACR), P501S (prostein), and prostate-specific membrane antigen (PSMA). Residual carcinoma was detected in 250 histological slides of 42 patients in a total of 497 slides from 45 patients. In five of 250 slides (2%), carcinoma was not able to be recognized on HE-stained slides, but was found on the immunohistochemistry slides. PSMA had reacted positively beyond a moderate degree in carcinoma from all patients. PSA was positive for carcinoma in most of the patients, while negative or minimal staining was observed in a small number of patients. Carcinoma was positively reactive with P504S and P501S in most of the patients, but was negatively reactive in a few. The Gleason score for a pretreatment needle biopsy correlated with P504S staining of the prostatectomy specimens. P504S and P501S had limited ability to identify degenerated carcinoma. PSMA was the most useful marker to identify carcinoma after hormone therapy.
Pathology International 12/2008; 58(11):687-94. · 1.62 Impact Factor
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Mitsuhide Noshiro,
Emiko Usui,
Takeshi Kawamoto, Fuyuki Sato,
Ayumu Nakashima,
Taichi Ueshima,
Kiyomasa Honda,
Katsumi Fujimoto,
Sato Honma,
Ken-ichi Honma,
Makoto Makishima,
Yukio Kato
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ABSTRACT: DEC1 (BHLHB2/Stra13/Sharp2)-a basic helix-loop-helix transcription factor-is known to be involved in various biological phenomena including clock systems and metabolism. In the clock systems, Dec1 expression is dominantly up-regulated by CLOCK : BMAL1 heterodimer, and it exhibits circadian rhythm in the suprachiasmatic nucleus (SCN)-the central circadian pacemaker-and other peripheral tissues. Recent studies have shown that the strong circadian rhythmicity of Dec1 in the SCN was abolished by Clock mutation, whereas that in the liver was affected, but not abolished, by Clock mutation. Moreover, feeding conditions affected hepatic Dec1 expression, which indicates that Dec1 expression is closely linked with the metabolic functions of the liver. Among ligand-activated nuclear receptors examined, LXRalpha and LXRbeta with T0901317-agonist for LXR-were found to be potent enhancers for Dec1 promoter activity, and a higher expression level of LXRalpha protein was detected in the liver than in the kidney and heart. T0901317 increased the levels of endogenous Dec1 transcript in hepatoma cells. Chromatin immunoprecipitation assay indicated that LXRalpha bound to the Dec1 promoter, and an LXRalpha-binding site was identified. These observations indicate that hepatic DEC1 mediates the ligand-dependent LXR signal to regulate the expression of genes involved in the hepatic clock system and metabolism.
Genes to Cells 12/2008; 14(1):29-40. · 2.68 Impact Factor
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ABSTRACT: Claudin-1 is a membrane protein with four transmembrane domains, that is exclusively localized at cellular tight junctions. Recent studies have reported that claudin-1 plays an important role in cancer invasion and metastasis. However, the significance of claudin-1 in pancreatic cancer is still unknown. In the present study, we investigated the role of claudin-1 expression in pancreatic cancer growth using the PANC-1 human pancreatic cancer cell line. Treatment with tumor necrosis factor-alpha (TNF-alpha), an inflammatory cytokine, resulted in increased detection of 89 kDa products of poly-(ADP-ribose) polymerase (PARP), a marker of apoptosis, and decreased PANC-1 cell proliferation by 23%. Expression of claudin-1 was up-regulated by TNF-alpha in a concentration-dependent manner in PANC-1 cells. PANC-1 cells treated with TNF-alpha and siRNA against claudin-1 showed a 15% increase in proliferation; i.e. the cells transfected with siRNA against claudin-1 showed resistance to TNF-alpha-induced apoptosis. These results suggest that claudin-1 expression is responsible for TNF-alpha-dependent growth signals and the proliferation of pancreatic cancer cells.
International Journal of Molecular Medicine 12/2008; 22(5):645-9. · 1.98 Impact Factor
