Proton Beam Therapy for Hepatocellular Carcinoma Adjacent to the Porta Hepatis

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• 作者：Masashi Mizumoto ; Koichi Tokuuye ; Shinji Sugahara ; Hidetsugu Nakayama ; Nobuyoshi Fukumitsu ; Kiyoshi Ohara ; Masato Abei ; Junichi Shoda ; Eriko Tohno ; Manabu Minami
• 关键词：Proton beam therapy ; Hepatocellular carcinoma ; Porta hepatis ; Survival ; Control
• 刊名：International Journal of Radiation Oncology*Biology*Physics
• 出版年：2008
• 出版时间：1 June 2008
• 年：2008
• 卷：71
• 期：2
• 页码：462-467
• 全文大小：178 K

文摘

_2A-adrenoceptors are expressed on intestinal cells and they participate in the control of epithelial functions such as solute and water transport or cell proliferation. In pathological conditions, pro-inflammatory cytokines secreted by lymphocytes are responsible for modification of intestinal cell characteristics including phenotype switch and changes in the expression of pumps and ion channels. Using the HT29 cell line as a model, the present work examined the effect of two inflammatory cytokines, interferon-γ (IFNγ) and tumor necrosis factor- (TNF), on the expression of the human _2A-adrenoceptor. Exposure of cells to either IFNγ or TNF resulted in a concentration- and time-dependent diminution of [³H]RX821002 binding sites, which is preceded by a large decrease in the amount of _2A-adrenoceptor mRNA. The cytokines did not affect the receptor mRNA half-life, but inhibited the activity of a luciferase construct containing the promoter region of _2A-adrenoceptor gene, indicating that a decrease in the transcription rate is primarily responsible for the diminution of receptor expression. Exposure of cells to either IFNγ or TNF caused increased production of reactive oxygen species and transient phosphorylation of extracellular signal-regulated kinase (Erk1/2). The effect of cytokines was mimicked by H₂O₂ but was unaffected by the addition of anti-oxidants. The blockade of Erk1/2 activation by PD98059 blunted the effect of TNF but not of IFNγ. In conclusion, the present findings demonstrate that IFNγ and TNF diminish the _2A-adrenoceptor expression in HT29 cells by decreasing the transcription rate without modifying the stability of mRNA. The transcription inhibition is however triggered via different signalling pathways. The results suggest that cytokine-mediated down-regulation of _2A-adrenoceptor could contribute to the pathogenesis of inflammatory bowel disease.