Role of CCAT/enhancer binding protein (C/EBP) α and C/EBP β in carcinogenesis. of hepatoblastoma and differentiation of hepatoblast.

CCAT/增强子结合蛋白 (C/EBP) α 和 C/EBP β 在肝母细胞瘤发生和肝母细胞分化中的作用。

• 批准号: 14570726
• 负责人: TOMIZAWA Minoru
• 金额: $ 2.56万
• 依托单位: Chiba University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2002
• 资助国家: 日本
• 起止时间: 2002 至 2003
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14570726/
• 关键词: hepatoblastoma; diagnosis; Cox hazard model; epatocyte differentiation; prognosis; transcription factor; C; EBP α; EBP β; 肝芽腫; 肝癌; 肝芽細胞; 肝細胞分化; 転写因子; リアルタイム定量PCR; アデノウィルスベクター; 遺伝子治療

Background & Aims : Hepatoblastoma (HB) occurs from differentiation arrest of hepatocyte at hepatoblast. We analyzed the expression of CCAAT/enahncer binding protein (C/EBP)α and C/EBPβ that promote hepatocyte differentiation and inhibit proliferation of hepatocytes. Methods : Real-time quantitative PCR was performed to compare the expression of C/EBPα and C/EBPβ between tumor and non-tumor. Their expression was also analyzed Ath immunostaining. The expression levels of C/EBPα and C/EBPβ, were compared with clinoco-pathological data. Results : C/EBPα was up-regulated 2.23 times (P=0.013) and C/EBPβ was down-regulated 27% (P=0.002) in tumor as compared with non-tumor, as confirmed with immunostaining. C/EBPα was more up-regulated and C/EBPβ more down-regulated in poor differentiated part than well differentiated one in the same HB tumor immunohistochemically. Patients with higher expression of C/EBPα (P=0.05), and lower expression of C/EBPβ (P=0.025) than each median showed poor prognosis, respectively. With proportional Cox hazard model, hazard ratio of higher expression of C/EBPα, C/EBPβ, and poorly differentiated type were 3.57 (95% confidential interval, 0.91-14.0, P=0.068), 0.20 (0.04-0.96, P=0.044), and 13.5 (1.70-107, P=0.014), respectively. Conclusion : The analysis of expression of CIEBPα and C/EBPβ may be useful for precise diagnosis and prediction of prognosis of HB patients. CIEBPα may not act as a tumor suppressor in HB while C/EBPβ does. Since both C/EBPα and C/EBPβ promote hepatocyte differentiation, down-regulation of C/EBPβ led to the differentiation arrest and cell proliferation, and C/EBPα was up-regulated to compensate the role of C/EBPβ in hepatocyte differentiaion.

背景与目的：肝母细胞瘤（HB）发生于肝细胞分化阻滞。我们分析了促进肝细胞分化和抑制肝细胞增殖的CCAAT/增强子结合蛋白(C/EBP)α和C/EBPβ的表达。方法：采用实时荧光定量PCR法比较肿瘤组织与非肿瘤组织中C/EBPα和C/EBPβ的表达。免疫染色分析其表达。C/EBPα和C/EBPβ的表达水平与临床病理数据进行比较。结果：经免疫染色证实，肿瘤组织中C/EBPα比非肿瘤组织上调2.23倍（P=0.013）， C/EBPβ下调27% （P=0.002）。在相同的HB肿瘤中，C/EBPα在低分化部位比高分化部位表达上调，C/EBPβ表达下调。C/EBPα表达较高（P=0.05）、C/EBPβ表达较低（P=0.025）的患者预后较差。采用比例Cox风险模型，高表达C/ ebbp α、高表达C/ ebbp β和低分化型的风险比分别为3.57（95%可信区间0.91 ~ 14.0，P=0.068）、0.20 （0.04 ~ 0.96，P=0.044）和13.5 （1.70 ~ 107，P=0.014）。结论：分析CIEBPα和C/ eebp β的表达可用于HB患者的准确诊断和预后预测。在HB中，CIEBPα可能不作为肿瘤抑制因子，而C/EBPβ可以。由于C/EBPα和C/EBPβ均促进肝细胞分化，下调C/EBPβ导致分化阻滞和细胞增殖，上调C/EBPα补偿C/EBPβ在肝细胞分化中的作用。

项目成果

Tomizawa M, (2名), Nakagawara A, (1名): "Downregulated expression of the CCAAT/enhancer binding protein a and b genes in human hepatocellcularcarcinoma : a possible prognostic marker"Anti-cancer Res.. (印刷中).

Tomizawa M（2 人）、Nakakawara A（1 人）：“人肝细胞癌中 CCAAT/增强子结合蛋白 a 和 b 基因的表达下调：可能的预后标志物”Anti-cancer Res..（出版中）。

Tomizawa M, (4名), Nakagawara A, (1名): "Expression of the CCAAT/enahncer binding protein α gene, involved in hepatocyte proliferation, was decreased in human hepatocellular carcinoma"Int. J. Mol. Med.. 9巻6号. 597-600 (2002)

Tomizawa M（4 人）、Nakakawara A（1 人）：“参与肝细胞增殖的 CCAAT/增强子结合蛋白 α 基因的表达在人肝细胞癌中降低”Int. J. Mol. 9。第 6 卷. 597-600 (2002)