GENOMIC MECHANISMS OF REGULATION AND CONTROL OF HEPATOCARCINOGENESIS BY RETINOIDS

类维生素a抑制多步骤癌变的肿瘤促进期。我们对类维甲酸对肝细胞癌的化学预防进行了研究，最近证实了无环类维甲酸对第二原发性肝癌发生的临床作用（国际肝病杂志3:S4,1995）。澄清类维生素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理论基础至关重要。在本研究中，我们利用小鼠肝癌发生模型和人肝癌来源细胞系，阐明了两种可能的类维甲酸作用机制；分化诱导和细胞凋亡诱导。前一种机制是由类视黄酮与核类视黄酮受体结合开始的信号发挥作用（Mol Carcinogenesis 10: 151-158,1994）。后一种机制是通过干扰素阻断转化生长因子- α的自分泌/旁分泌回路来发挥作用的（生物化学，生物物理学报，2007:382-388,1995）。我们扩展了我们的研究，然后开发新的类维甲酸化合物，基于发现类维甲酸的作用之一是在基因组水平上发挥作用，如上所述。我们利用它们与维甲酸X受体的结合亲和力作为标记筛选了几种可能的化合物，并确定了三个新的候选化合物（Biochem Biophys commin 209: 66-72,1995）。我们认为这些结果对建立类维生素a的癌症化学预防和开发新的癌症化学预防药物非常重要。

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.