RECEPTOR DYSFUNCTION AND CANCER CHEMOPREVENTION BY RETINOID AND INTERFERON

我们研究了类雷维酮对肝细胞癌（HCC）的化学预防作用，并证实了无环类雷维酮对第二原发性肝癌发生的临床疗效。无环类维甲酸通过根除肝脏转化细胞的癌前和潜伏恶性克隆来防止肝癌的发生。我们在细胞水平上证明了这种克隆缺失的机制。我们发现无环类维甲酸不仅与核受体结合，而且还影响膜受体。无环类维甲酸增强干扰素(IFN)-β和IFN-α的抗肿瘤作用，而天然维甲酸（全反式和9-顺式维甲酸）则没有这种作用。这种联合效应可能是由于以DNA片段化和染色质凝聚为特征的细胞凋亡诱导增强。用无环类维甲酸预处理HCC细胞后再用IFN-β，而不是相反，诱导了这种细胞毒性作用。无环类维甲酸增加了1型IFN受体（IFNR）的表达，并与抗1型IFNR抗体包涵消除了联合作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实在在的好处。我们还证明了医院信息系统对癌症化学预防的转化研究是有用的。我们认为这些结果对建立化学预防癌症和开发新的癌症化学预防药物具有重要意义。

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.