Acyclic retinoid in the chemoprevention of hepatocellular carcinoma (review).
Acyclic retinoid in the chemoprevention of hepatocellular carcinoma (review).
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DOI：
10.3892/ijo.24.4.797
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发表时间：
2004-04
影响因子：
5.2
通讯作者：
S. Kojima;M. Okuno;R. Matsushima-Nishiwaki;S. Friedman;H. Moriwaki
中科院分区：
文献类型：
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作者：
S. Kojima;M. Okuno;R. Matsushima-Nishiwaki;S. Friedman;H. Moriwaki
我们在这里回顾了一种合成的类维生素A类似物（维生素A及其衍生物），称为无环类维生素A（AR），在肝细胞癌（HCC）的化学预防中的治疗应用及其潜在的分子机制。治疗后复发率高已成为HCC预后的主要决定因素，尤其是肝炎病毒感染的肝硬化患者。口服补充 AR 成功地预防了 HCC 复发，这与血清凝集素反应性甲胎蛋白 (AFP-L3) 水平的消失有关，AFP-L3 是肝脏中隐匿性癌症克隆的标志物，这表明患者肝脏中潜在的恶性克隆已被根除。这给我们带来了一个新的概念，即以 AR 作为药物的“克隆删除”，其概念与癌症化疗类似。肝硬化患者的 HCC 含有较低水平的内源性视黄酸，同时由于其核受体视黄酸 X 受体 α (RXRalpha) 的功能障碍，对视黄酸 (RA) 不敏感。在 HCC 组织中，RXRα 在细胞外信号调节激酶 (Erk) 的作用下被组成型磷酸化，从而失去其反式激活活性，并通过泛素/蛋白酶体途径对降解产生抗性。这导致磷酸灭活的 RXRα 的积累，其作为显性负性受体发挥作用，并通过保持正常的 RXRα 来干扰反式激活。 AR（而非天然 RA）可阻止 RXRalpha 的磷酸化，并通过下调 Ras/Erk 系统恢复 RXRalpha 的功能，使 HCC 细胞对内源性配体 9-cis-RA 敏感。这可能通过诱导生长抑制剂如p21CIP1和/或细胞凋亡诱导剂（包括组织转谷氨酰胺酶）与半胱天冬酶依赖性和非依赖性细胞凋亡相关。 AR还增强HCC细胞对干扰素α和β的敏感性，从而间接促进这些干扰素诱导的细胞凋亡。总之，我们的临床经验和基础研究共同为使用 AR 进行 HCC 化学预防提供了强有力的理由。
We here review therapeutic application of a synthetic analog of retinoids (vitamin A and its derivatives), named acyclic retinoid (AR), towards chemoprevention of hepatocellular carcinoma (HCC), and its underlying molecular mechanisms. A high incidence of post-therapeutic recurrence has become a major determinant of the prognosis of HCC, especially in the patients of hepatitis virus-infected cirrhosis. Oral supplementation of AR successfully prevented the recurrence of HCC, associated with a disappearance in serum levels of lectin-reactive alpha-fetoprotein (AFP-L3), a marker of occult cancer clones in the liver, suggesting eradication of latent malignant clones from patients' liver. This led us a novel concept of 'clonal deletion' with AR as an agent that is conceptually similar to cancer chemotherapy. HCC in cirrhotic patients contains lower levels of endogenous retinoids and simultaneously is insensitive to retinoic acid (RA) because of malfunction of its nuclear receptor, retinoid X receptor alpha (RXRalpha). In HCC tissues, RXRalpha is constitutively phosphorylated by the action of extracellular signal-regulated kinase (Erk), thereby losing its transactivation activity and becoming resistant to degradation via ubiquitin/proteasome pathway. This leads to accumulation of phospho-inactivated RXRalpha, that functions as a dominant negative receptor and interferes with transactivation by remaining normal RXRalpha. AR but not natural RA prevents phosphorylation of RXRalpha and restores the function of RXRalpha via down-regulating Ras/Erk system, making HCC cells sensitive to the endogenous ligand, 9-cis-RA. This may link to both caspase-dependent and -independent apoptosis of the cancer cells via induction of growth suppressor(s) such as p21CIP1 and/or apoptosis inducer(s) including tissue transglutaminase. AR also enhances the sensitivity of HCC cells to interferons-alpha and -beta, and thereby indirectly promotes apoptosis induced by these interferons. In summary, our clinical experience and basic research together provide a strong rationale to use AR in the chemoprevention of HCC.