Strategy for the chemoprevention of hepatocellular carcinoma by targeting phosphorylated RXRa

靶向磷酸化 RXRa 的肝细胞癌化学预防策略

• 批准号: 17015016
• 负责人: MORIWAKI Hisataka
• 金额: $ 50.88万
• 依托单位: Gifu University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research on Priority Areas
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2009
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17015016/
• 关键词: 核内受容体; 分子標的; 化学予防; 肝臓癌; レチノイド; 肺発癌予防; 核内受容体修飾異常; リン酸化・非リン酸化RXR; 非環式レチノイド; 肝発癌予防

A malfunction of RXRα due to phosphorylation by activation of the Ras/MAPK and PI3K/Akt signaling pathways is profoundly associated with the development of HCC and thus may be a critical target for HCC chemoprevention. A phase II/III trial of acyclic retinoid (ACR), which targets phosphorylated RXRα, to test its effectiveness in preventing second primary HCC in hepatitis C virus-positive patients is currently underway in Japan as a large-scale randomized placebo-controlled trial. In the present study, the combination of ACR plus specific agent, which targets growth factor receptors, the Ras/MAPK and PI3K/Akt signaling pathways, inhibit the RXRα phosphorylation and it may therefore be a promising strategy to prevent the development of HCC. These findings suggest that the inhibition of RXRα phosphorylation and the restoration of its physiological function as a master regulator for nuclear receptors may be a potentially effective strategy for HCC chemoprevention and treatment.

通过激活RAS/MAPK和PI3K/AKT信号通路引起的RXRα的故障与HCC的发展密切相关，因此可能是HCC化学预防的关键靶标。针对磷酸化RXRα的丙烯酸类视网膜类似（ACR）的II/III期试验，以测试其在丙型肝炎病毒阳性患者中预防第二次原发性HCC方面的有效性，目前在日本正在作为一项大规模随机安慰剂对照试验。在本研究中，靶向生长因子受体，RAS/MAPK和PI3K/AKT信号通路的ACR Plus特异性药物的组合抑制了RXRα磷酸化，因此可能是防止HCC发展的承诺策略。这些发现表明，抑制RXRα磷酸化及其作为核受体的主要调节剂的身体功能的恢复可能是HCC化学预防和治疗的潜在有效策略。

项目成果

Alteration of gene expression in human hepatocellular carcinoma with integrated hapatitis B virus DNA.

整合乙型肝炎病毒 DNA 的人肝细胞癌中基因表达的改变。

• 发表时间: 2005
• 期刊: Clin Cancer Res 11
• 作者: Nishiguchi;S.;et al.
• 通讯作者: et al.

Oncostain M Gene Therapy Attenuates Liver Damage Induced by Dimethylnitrosamine in Rats

Oncostain M 基因疗法可减轻二甲基亚硝胺引起的大鼠肝损伤

• 发表时间: 2007
• 期刊: Am.J.Pathol. 171
• 作者: Kotsuma Y.;et.al.;Hamada T
• 通讯作者: Hamada T

Synergistic growth inhibition by acyclic retinoid and vitamin K2 in human hepatocellular carcinoma cells

• DOI: 10.1111/j.1349-7006.2006.00384.x
• 发表时间: 2007-03-01
• 期刊: CANCER SCIENCE
• 影响因子: 5.7
• 作者: Kanamori, Toh;Shimizu, Masahito;Moriwaki, Hisataka
• 通讯作者: Moriwaki, Hisataka

Prevention of rat hepatocarcinogenesis by acyclic retinoid is accompanied by reduction in emergence of both TNF-a- expressing oval-like cells and activated hepatic stellate cells.

无环类维生素A预防大鼠肝癌的发生伴随着表达TNF-α的卵圆样细胞和活化的肝星状细胞的出现的减少。

• 发表时间: 2005
• 期刊: Nutr Cancer 51
• 作者: Sano T;Kojima S;Moriwaki H;Tanaka T;(他11名)
• 通讯作者: (他11名)

Ursodeoxycholic acid inhibits colitis-related colon carcinogenesis in mice:A comparative study regarding the effect of sulphasalazine

熊去氧胆酸抑制小鼠结肠炎相关结肠癌的发生：柳氮磺胺吡啶作用的对比研究

• 发表时间: 2007
• 期刊: Clin.Cancer Res. 13
• 作者: Miyoshi Y.;et.al.;Kohno H
• 通讯作者: Kohno H