MECHANISMS OF CLONAL DELETION OF HEPATOCELLULAR CARCINOMA BY ACYCLICRETINOID

环状维A酸克隆删除肝细胞癌的机制

• 批准号: 10557055
• 负责人: MORIWAKI Hisataka
• 金额: $ 3.78万
• 依托单位: GIFU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-10557055/
• 关键词: CANCER CHEMOPREVENTION; HEPATOCELLULAR CARCINOMA; RETINOID; RETINOID X RECEPTOR; DIFFERENTIATION INDUCTION; APOPTOSIS; CASPASE; レチノイドX受容体; 遺伝子変異

Retinoid inhibit the tumor promotion phase of mutistep carcinogenesis. We have conducted investigations of chemoprevention of hepatocellular carcinoma by retionoids and confirmed the clinical effects of acyclic retionid on second primary hepatocarcinogenesis (New Engl J Med, 1996). Moreover, we reveled significant difference in the survival rate between the retinoid and the placebo groups with a median follow-up of 62 months (P=0.04). Among selected patients variables at the time of randomization, proportional hazards analysis revealed that the administration of acyclic retinoid was the only independent factor that significantly improved survival of the patients. The estimated relative risk of death was 0.3 (95 percent confidence interval, 0.1 to 0.8) in the acyclic retinoid group as compared with the placebo group (New Engl J Med, 340 : 1046-1047 ; 1999).Acyclic retinoid prevents hepatocarcinogenesis by eradicating premalignant and latent malignant clones of transformed cells from the liver. We demonstrate the mechanism of this clonal deletion at the cellular level. Production of albumin was recovered while that of AFP-L3 was reduced after exposure of the cells to acyclic retinoid for 2 days. In parallel, both TERT mRNA expression and telomerase activity were down-regulated. The cells subsequently died due to apoptosis. Serial increases in mitochondrial membrane permeability and caspase-9 and -3 activities induced apoptosis. Acyclic retinoid first induces differentiation and reduces telomerase activity. Subsequent late apoptosis completes the clonal deletion of the cells.We evaluate these results as very important to establish cancer chemoprevention with retionids and to develop novel cancer chemopreventive agents.

维甲酸抑制多步骤癌变的肿瘤促进阶段。我们已经进行了类维生素A化学预防肝细胞癌的研究，并证实了非环类维生素A对第二原发性肝癌发生的临床作用（New Engl J Med，1996）。此外，我们发现维甲酸组和安慰剂组的生存率有显著差异，中位随访时间为62个月（P=0.04）。在随机化时选定的患者变量中，比例风险分析显示，给予非环类维生素A是显著改善患者生存率的唯一独立因素。与安慰剂组相比，无环类维生素A组估计的相对死亡风险为0.3（95%置信区间，0.1 - 0.8）（New Engl J Med，340：1046-1047 ; 1999）。我们在细胞水平上证明了这种克隆缺失的机制。白蛋白的产生恢复，而AFP-L3的细胞暴露于无环类维生素A 2天后减少。同时，TERTmRNA表达和端粒酶活性均下调。细胞随后由于凋亡而死亡。线粒体膜通透性和caspase-9和-3活性的连续增加诱导细胞凋亡。无环类维生素A首先诱导分化并降低端粒酶活性。随后的晚期凋亡完成了细胞的克隆性缺失。我们评价这些结果对于建立用retionids的癌症化学预防和开发新的癌症化学预防剂非常重要。

项目成果

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