Induction of hepatocyte proliferation by retinoic acid
Induction of hepatocyte proliferation by retinoic acid
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DOI：
10.1093/carcin/bgh221
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发表时间：
2004-11-01
期刊：
影响因子：
4.7
通讯作者：
Columbano, A
中科院分区：
文献类型：
--
作者：
Ledda-Columbano, GM;Pibiri, M;Columbano, A
类维生素A已被证明可以通过抑制细胞周期、诱导细胞凋亡和/或分化发挥抗癌作用。特别是在大鼠肝脏中，视黄酸已被证明可以抑制部分肝切除术后的再生，最有可能是通过抑制 c-fos 和 c-jun 的表达。令人惊讶的是，尽管全反式视黄酸 (tRA) 具有治疗作用，但尚无关于其对正常成人肝脏影响的数据。在这里，我们发现，饮食中添加 tRA（150 mg/kg）在第 1 周和第 2 周增加了小鼠肝脏中的 DNA 合成，并在第 4 周时恢复到对照值（标记指数分别为 16.5、8.3 和 3.3%，而对照值为 1.4、1.3 和 2.5%）。有丝分裂指数的增加与溴脱氧尿苷掺入平行。动力学研究表明，进入S期在24至48小时之间开始，在96至120小时之间达到高峰。肝脏的组织学观察和血清谷氨酸-丙酮酸转氨酶水平的生化评估没有发现任何细胞死亡的证据，这表明DNA合成的增加不是由于tRA诱导的肝脏损伤和再生，而是直接促有丝分裂作用的结果。此外，7天治疗后的总肝DNA含量分析显示，与对照组相比，tRA喂养的小鼠显着增加（tRA喂养的小鼠为21.11 mg/100 g体重，对照为15.67 mg/100 g体重）。 tRA 喂养小鼠的肝细胞增殖与肝脏细胞周期蛋白 D1、E 和 A 水平增加以及 pRb 家族成员 p107 表达增强相关。总之，结果表明，与类固醇/甲状腺激素核受体超家族的其他配体类似，tRA 在没有细胞死亡的情况下诱导肝细胞增殖。 tRA 的促有丝分裂作用提示其在肝癌发生中可能用于抗肿瘤目的。
Retinoids have been shown to exert an anticarcinogenic effect through suppression of the cell cycle, induction of apoptosis and/or differentiation. In rat liver, in particular, retinoic acid has been shown to inhibit regeneration after partial hepatectomy, most probably through repression of the expression of c-fos and c-jun. Surprisingly enough, in spite of the proposed therapeutic effects of all-trans retinoic acid (tRA) no data are available on its effect on normal adult liver. Here, we show that tRA administration in the diet (150 mg/kg) increased DNA synthesis in mouse liver, at 1 and 2 weeks, with a return to control values at 4 weeks (labelling index was 16.5, 8.3 and 3.3%, respectively, versus control values of 1.4, 1.3 and 2.5%). Increase in mitotic index paralleled that of bromodeoxyuridine incorporation. Kinetic studies showed that entry into S phase began between 24 and 48 h, with a peak between 96 and 120 h. Histological observation of the liver and biochemical evaluation of the levels of serum glutamate-pyruvate transaminases did not reveal any evidence of cell death demonstrating that increased DNA synthesis was not due to tRA-induced liver damage and regeneration, but rather the consequence of a direct mitogenic effect. In addition, analysis of total hepatic DNA content after a 7-day treatment showed a significant increase in tRA-fed mice compared with controls (21.11 mg/100 g body wt in tRA-fed mice versus 15.67 mg/100 g body wt of controls). Hepatocyte proliferation in tRA-fed mice was associated with increased hepatic levels of cyclin D1, E and A, and enhanced expression of the member of pRb family, p107. In conclusion, the results showed that tRA induces hepatocyte proliferation in the absence of cell death, similarly to other ligands of steroid/thyroid hormone nuclear receptor superfamily. The mitogenic effect of tRA cautions about its possible use for antitumoral purposes in liver carcinogenesis.