| Co-Investigator(Kenkyū-buntansha) |
IMAMURA Masayuki Kyoto University, Graduate School of Medicine, Department of Surgery & Surgical Basic Science, Professor, 医学研究科, 教授 (00108995)
MAEDA Masato Kyoto University, Graduate School of Medicine, Department of Surgery & Surgical Basic Science, Instructor, 医学研究科, 助手 (10314220)
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| Budget Amount *help |
¥10,300,000 (Direct Cost: ¥10,300,000)
Fiscal Year 2001: ¥4,400,000 (Direct Cost: ¥4,400,000)
Fiscal Year 2000: ¥5,900,000 (Direct Cost: ¥5,900,000)
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| Research Abstract |
Interferon gamma as well as EGF inhibited the growth of esophageal cancer cells in 50% of the cell lines.STAT1 dominant negative cells demonstrated that this inhibitory effect was dependent on the STAT1. STATsignaling pathway was not harmful and induced Involculin in the normal esophageal squamous cell (NESC). In the KYSE70 cell which was not inhibited by EGF and INF gamma, hospholylation of the EGFR was not observed and the lack of INF gamma receptor was demonstrated. The growth of xeno-transplanted cells were inhibited by INF gamma and bioassay using explant culture was being checkedto predict INFgamma sensitivity.
A specific ligand of PPARγ, troglitazone, led to G1 accumulation with the increase in p27 (Kip1), butnot p21 (Waf1/Cip1), and inhibited cellular proliferation in a pancreatic cancer cell line, Panc-1. The overexpression of PPARγ in a pancreatic cancer cell line, KMP-3, caused lipid accumulation, which suggested cell growth in some cancers might be inhibited, at least in par
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t, through terminal differentiation in the adipogenic lineage. In addition, implanted Panc-1 tumors in nude mice showed significant inhibition of tumor growth, when treated with pioglitazone, another specific ligand of PPARγ.
RT-PCR andwestern blot analysis demonstrated that all ten tested human esophageal SCCcells, KYSE series, expressed PPAR gamma and RXR alfa. In luciferase assay, both troglitazone and pioglitazone transactivated the transcription of a peroxisome proliferator response element-driven promoter in a dose dependent fashion and when applied with 9-cis retinoic acid (9CRA), relative luciferase ctivity was elevated more strongly. Troglitazone inhibited growth of all ten tested cell lines where as pioglitazone inhibited 6 of these cell lines. In KYSE270 cells, cell cycle analysis by flow cytometry demonstrated that TZDs and 9CRA increased subG1 phase. Poly (ADP-ribose) polymerase (PARP) protein cleavage band was observed in the cells treated with TZDs and 9CRA. PARP cleavage band appeared at an early time point in the cells treated with both troglitazone and 9CRA, compared with pioglitazone and 9CRA simultaneously applied cells. P27 protein expression was increased to only the cells reated with both troglitazone and 9CRA. Simultaneous treatment of TZD and 9CRA is a promising therapeutic strategy of human esophageal squamous cell carcinoma. Less
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