RECEPTOR DYSFUNCTION AND CANCER CHEMOPREVENTION BY RETINOID AND INTERFERON

我们研究了维甲酸类化合物对肝细胞癌的化学预防作用，并证实了非环类维甲酸对第二原发癌发生的临床效果。去环维A酸通过根除肝脏转化细胞的癌前克隆和潜在恶性克隆来预防肝癌的发生。我们在细胞水平上证明了这种克隆缺失的机制。我们发现，去环维A酸不仅与核受体结合，而且还影响膜受体。非环维A酸不仅能增强干扰素-β和干扰素-α的抗肿瘤作用，天然维甲酸(全反式和9-顺式维甲酸)则不能增强其抗肿瘤作用。这种联合作用可能是由于增强了以DNA片段化和染色质凝集为特征的细胞凋亡诱导。用去环维A酸预处理肝癌细胞后再用干扰素-β，而不是相反，诱导了这种细胞毒效应。非环类维甲酸增加了1型干扰素受体(IFNR)的表达，并与抗1型IFNR抗体包合，取消了联合应用对生长的协同抑制作用。医院信息系统为临床研究带来了实质性的好处。我们还证明了医院信息系统对癌症化学预防的转译研究是有用的。我们评价这些结果对于建立用类固醇进行的癌症化学预防和开发新的癌症化学预防药物非常重要。

We have conducted investigations of chemoprevention of hepatocellular carcinoma (HCC) by retionoids and confirmed the clinical effects of acyclic retionid on second primary hepatocarcinogenesis. 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. We revealed that acyclic retinoid not only binds to nuclear receptors, but also affects membrane receptors. Acyclic retinoid enhanced anti-tumor effects of not only interferon (IFN)-β but also IFN-α, however, natural retinoic acid (all-trans and 9-cis retinoic acid) failed to exert such effect. This combination effect was likely due to enhanced apoptosis induction as characterized by DNA fragmentation and chromatin condensation. Pretreatment of the HCC cells with acyclic retinoid followed by IFN-β, but not the converse, induced such cytotoxic effect. Acyclic retinoid increased the expression of type 1 IFN receptor (IFNR) and inclusion with anti-type 1 IFNR antibody abolished the synergistic growth suppression by the combination.The hospital information system brings substantial benefits to clinical study. We also demonstrate that the hospital information system is useful for translational study of cancer chemoprevention.We evaluate these results as very important to establish cancer chemoprevention with retionids and to develop novel cancer chemopreventive agents.