GENOMIC MECHANISMS OF REGULATION AND CONTROL OF HEPATOCARCINOGENESIS BY RETINOIDS

类维生素A调控肝癌发生的基因组机制

• 批准号: 05670463
• 负责人: MORIWAKI Hisataka
• 金额: $ 1.41万
• 依托单位: GIFU UNIVERSITY
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (C)
• 财政年份: 1993
• 资助国家: 日本
• 起止时间: 1993 至 1995
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-05670463/
• 关键词: CANCER CHEMOPREVENTION; HEPATOCELLULAR CARCINOMA; RETINOIDS; CHEMICAL STRUCTURE; RETINOIC ACID RECEPTOR; RETINOID X REECEPTOR; DIFFERENTIATION INDUCTION; APOPTOSIS; 肺癌

Retinoids inhibit the tumor promotion phase of mutistep carcinogenesis. We have conducted investigations of chemoprevention of hepatocellular carcinoma by retinoids and recently confirmed the clinical effects of acyclic retinoid on second primary hepatocarcinogenesis (Internat'l Hepatol Commun 3 : S4,1995). Clarification of the mechanisms of such action of retinoids is essential to establish the ratiomale for prevention of various carcinomas including hepatocellular carcinoma.In the present study using murine model of hepatocarcinogenesis and human hepatoma-derived cell lines, we have elucidated two possible mechanisms of retinoid action ; differentiation induction and apoptosis induction. The former mechanism was exerted by a signal which started with the binding of retinoid with nuclear retinoid receptors (Mol Carcinogenesis 10 : 151-158,1994). The latter mechanism was exerted via interruption of autocrine/paracrine loop of transforming growth factor-alpha by ratinoid (Biochem Biophys Res Commun 207 : 382-388,1995).We extended our study then to develop novel retinoid compounds, being based on the finding that one of retinoid action was exerted at the genomic level as mentioned above. We screened several possible compounds using binding affinity of them with retinoid X receptor as a marker, and identified three new candidates (Biochem Biophys Res Commun 209 : 66-72,1995).We evaluate these results as very important to establish cancer chemoprevention with retinoids and to develop novel cancer chemopreventive agents.

类维生素A抑制多步致癌作用的肿瘤促进阶段。我们进行了类维生素A化学预防肝细胞癌的研究，并且最近证实了无环类维生素A对第二原发性肝癌发生的临床效果(Internat'l Hepatol Commun 3：S4，1995)。阐明类维生素A的作用机制对于建立预防包括肝细胞癌在内的各种癌症的比例至关重要。在本研究中，使用小鼠肝癌发生模型和人肝癌细胞系，我们阐明了类维生素A作用的两种可能机制；分化诱导和凋亡诱导。前一种机制是由类维生素A与核类维生素A受体结合开始的信号发挥的(Mol Carcinogenesis 10：151-158，1994)。后一种机制是通过类视黄醇中断转化生长因子-α的自分泌/旁分泌环而发挥的(Biochem Biophys Res Commun 207:382-388,1995)。基于类视黄醇作用之一在基因组水平发挥的发现，我们随后扩展了我们的研究以开发新的类视黄醇化合物。我们利用它们与类视黄醇X受体的结合亲和力作为标记筛选了几种可能的化合物，并鉴定了三种新候选物(Biochem Biophys Res Commun 209:66-72,1995)。我们评估这些结果对于建立类视黄醇的癌症化学预防和开发新型癌症化学预防剂非常重要。

项目成果

Imamine T,Moriwaki H,et al: "Impaired synthesis of retinol-binding protein and transthyretin in rat liver with bile duct obstruction" Dig Dis Sci. (in press).

Imamine T、Moriwaki H 等人：“胆管阻塞的大鼠肝脏中视黄醇结合蛋白和运甲状腺素蛋白的合成受损”Dig Dis Sci。

Nakamura N: "Induction of apoptosis by acyclic retinoid in the human hepatoma-derived cell line,HUH-7." Biochem Biophys Res Commun. 207. 382-388 (1995)

Nakamura N：“无环类视黄醇在人肝癌细胞系 HUH-7 中诱导细胞凋亡。”

Miwa Y,Moriwaki H,et al: "Effect of branched-chain amino acid infusion on protein metabolism in rats with acute hepatic failure" Hepatology. 22. 291-296 (1995)

Miwa Y，Moriwaki H，等人：“支链氨基酸输注对急性肝衰竭大鼠蛋白质代谢的影响”肝病学。

Katsumura N,Moriwaki H,et al: "Suppression of mouse skin papilloma by canthaxanthin and E=-carotene in vivo : Possibility of the regression of tumorigenesis without being converted to retinoic acid" Nutr Cancer. (in press).

Katsumura N、Moriwaki H 等人：“体内角黄素和 E=-胡萝卜素对小鼠皮肤乳头状瘤的抑制：在不转化为视黄酸的情况下消退肿瘤发生的可能性”Nutr Cancer。

Nakamura N,Moriwaki H,et al: "Induction of apoptosis by acyclic retinoid in human hepatoma-derived cell line" HuH-7. Biochem Biophys Res Commun. 207. 382-388 (1995)

Nakamura N、Moriwaki H 等人：“在人肝癌细胞系中通过非环状维A酸诱导细胞凋亡”HuH-7。