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.

Ras/MAPK和PI 3 K/Akt信号通路的激活导致RXRα磷酸化的功能障碍与HCC的发生密切相关，因此可能是HCC化学预防的关键靶点。一项针对磷酸化RXRα的无环类维生素A（ACR）的II/III期试验目前正在日本进行，作为一项大规模随机安慰剂对照试验，以测试其在预防丙型肝炎病毒阳性患者的第二次原发性肝癌方面的有效性。在本研究中，ACR与靶向生长因子受体、Ras/MAPK和PI 3 K/Akt信号通路的特异性药物联合使用，可抑制RXRα磷酸化，因此可能是预防HCC发展的有希望的策略。这些发现表明，抑制RXRα磷酸化并恢复其作为核受体主要调节剂的生理功能可能是肝癌化学预防和治疗的潜在有效策略。

项目成果

Prevention of second primary tumors by an acyclic retinoid in patients with hepatocellular carcinoma - Updated analysis of the long-term follow-up data

• DOI: 10.1159/000082093
• 发表时间: 2005-01-01
• 期刊: INTERVIROLOGY
• 影响因子: 4.6
• 作者: Takai, K;Okuno, M;Moriwaki, H
• 通讯作者: Moriwaki, H

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

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.

Effect of long-term postoperative interferon therapy on intrahepatic recurrence and survival rate after resection of hepatitis C virus-related hepatocellular carcinoma

• DOI: 10.1159/000082098
• 发表时间: 2005-01-01
• 期刊: INTERVIROLOGY
• 影响因子: 4.6
• 作者: Nishiguchi, S;Tamori, A;Kubo, S
• 通讯作者: Kubo, S

Acyclic retinoid synergises with valproic acid to inhibit growth in human hepatocellular carcinoma cells.

• DOI: 10.1016/j.canlet.2009.05.019
• 发表时间: 2009-11
• 期刊: Cancer letters
• 影响因子: 9.7
• 作者: H. Tatebe;M. Shimizu;Y. Shirakami;Hiroyasu Sakai-;Y. Yasuda;H. Tsurumi;H. Moriwaki