REGULATION OF HEPATOCARCINOGENESIS BY ACYCLIC RETINOID

无环维A酸对肝癌发生的调节作用

基本信息

批准号：
11670490
负责人：
MORIWAKI Hisataka
金额：
$ 2.24万
依托单位：
GIFU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2001
项目状态：
已结题

项目摘要

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, a synthetic retinoid analog, on second primary hepatocarcinogenesis. Interferons ( IFNs )-α and - β also induce apoptosis of hepatocellular carcinoma ( HCC ) cells and are used clinically in the prevention of HCC. Acyclic retinoid enhanced anti-tumor effects of not only 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 Mnduction 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. Moreover, the retinoid up-regulated the expression and DNA-binding activity of STAT1, an intracellular signal transducing molecule of IFNR. Thus, acyclic retinoid seemed to enhance the sensitivity of HCC cells to IFN-β and thereby promoted the cancer cell death. These results suggest a future clinical use of the combination of acyclic retinoid and IFN-β in the biochemoprevention of HCC. We evaluate these results as very important to establish cancer chemoprevention with retionids and to develop novel cancer chemopreventive agents.

视网膜类似抑制突变的癌变的肿瘤促进阶段。我们已经通过视网膜固醇对肝细胞癌的化学预防进行了研究，并证实了循环术的临床作用（一种合成性类维生素类似物）对第二次原发性肝癌发生的临床作用。干扰素（IFNS）-α和-β还诱导肝细胞癌（HCC）细胞的凋亡，并在临床上用于预防HCC。无环性类视网膜类动物不仅增强了IFN-β的抗肿瘤作用，而且还增强了IFN-α的抗肿瘤作用，但是天然视黄酸（全反式酸和9-cis视黄酸）未能执行这种效果。这种组合效应可能是由于DNA片段化和染色质缩合的特征而增加的凋亡MNDUCTION。用无环性类维生素类动物对HCC细胞进行预处理，然后是IFN-β，但没有相反，诱导了这种细胞毒性作用。无环性类维生素类动物增加了1型IFN受体（IFNR）的表达，并包含抗型1 IFNR抗体通过组合消除了协同生长抑制。此外，类视感上调了STAT1的表达和DNA结合活性，STAT1是IFNR的细胞内信号转导分子。这，无环性类维生素类动物似乎增强了HCC细胞对IFN-β的敏感性，从而促进了癌细胞死亡。这些结果表明，在HCC的生物化学预防中，无环类维生素类似和IFN-β的结合将来临床使用。我们将这些结果评估对于用夺回剂建立癌症化学预防并开发新型癌症化学预防剂非常重要。

项目成果

期刊论文数量（73）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Nagaki,M., Sugivama,A., Osawa,Y., Naiki,T., Nakashima,S., Nozawa,Y., Moriwaki,H.f.: "Lethal hepatic apoptosis mediated by tumor necrosis factor receptor, unlike Fas-mediated apoptosis, requires hepatocyte sensitization in mice."J Hepatol. 31. 997-1005 (19

Nagaki,M.、Sugivama,A.、Osawa,Y.、Naiki,T.、Nakashima,S.、Nozawa,Y.、Moriwaki,H.f.：“肿瘤坏死因子受体介导的致死性肝细胞凋亡，与 Fas 介导的细胞凋亡不同

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Muto,Y, Moriwaki,H, Saito,A.: "Prevention of second primary tumors by an acyclic retinoicl in patients with hepatocellular carcinoma"N Engl J Med. 340. 1046-1047 (1999)

Muto，Y，Moriwaki，H，Saito，A.：“通过无环视黄醇预防肝细胞癌患者的第二原发肿瘤”N Engl J Med。

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Nagaki,M., Miki,K., Kim,YI., Ishiyama,H., Hirahara,I., Takahashi,H., Sugiyama,A., Muto,Y., Moriwaki,H.: "Development and characterization of a hybrid bioartificial liver using primary hepatocytes entrapped in a basement membrane matrix"Dig Dis Sci. 46. 10

Nagaki,M.、Miki,K.、Kim,YI.、Ishiyama,H.、Hirahara,I.、Takahashi,H.、Sugiyama,A.、Muto,Y.、Moriwaki,H.：“开发和表征

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Kimura,K., Ando,K., Tomita,E., Ohnishi,H., Ishikawa,T., Kakumu,S., Muto,Y., Moriwaki,H.: "Elevated intracellular IFN- γ- levels in circulating CD8+lymphocytes in patients with fulminant hepatitis"J Hepatol. 31. 579-583 (1999)

Kimura, K.、Ando, K.、Tomita, E.、Ohnishi, H.、Ishikawa, T.、Kakumu, S.、Muto, Y.、Moriwaki, H.：“细胞内 IFN-γ- 水平升高暴发性肝炎患者循环 CD8+ 淋巴细胞中的“J Hepatol. 31. 579-583 (1999)”