Institut Pasteur, Unité d'Oncogenèse et Virologie Moléculaire, France.
J Hepatol. 2012 Nov;57(5):1029-36. doi: 10.1016/j.jhep.2012.06.035. Epub 2012 Jul 11.
BACKGROUND & AIMS: The four and a half LIM-only protein 2 (FHL2) is upregulated in diverse pathological conditions. Here, we analyzed the effects of FHL2 overexpression in the liver of FHL2 transgenic mice (Apo-FHL2).
We first examined cell proliferation and apoptosis in Apo-FHL2 livers and performed partial hepatectomy to investigate high FHL2 expression in liver regeneration. Expression of FHL2 was then analyzed by real time PCR in human hepatocellular carcinoma and adjacent non-tumorous livers. Finally, the role of FHL2 in hepatocarcinogenesis was assessed using Apo-FHL2;Apc(lox/lox) mice.
Six-fold increase in cell proliferation in transgenic livers was associated with concomitant apoptosis, resulting in normal liver mass. In Apo-FHL2 livers, both cyclin D1 and p53 were markedly increased. Evidence supporting a p53-dependent cell death mechanism was provided by the findings that FHL2 bound to and activated the p53 promoter, and that a dominant negative p53 mutant compromised FHL2-induced apoptosis in hepatic cells. Following partial hepatectomy in Apo-FHL2 mice, hepatocytes displayed advanced G1 phase entry and DNA synthesis leading to accelerated liver weight restoration. Interestingly, FHL2 upregulation in human liver specimens showed significant association with increasing inflammation score and cirrhosis. Finally, while Apo-FHL2 mice developed no tumors, the FHL2 transgene enhanced hepatocarcinogenesis induced by liver-specific deletion of the adenomatous polyposis coli gene and aberrant Wnt/β-catenin signaling in Apc(lox/lox) animals.
Our results implicate FHL2 in the regulation of signaling pathways that couple proliferation and cell death machineries, and underscore the important role of FHL2 in liver homeostasis and carcinogenesis.
四个半 LIM 结构域只有 2 个（FHL2）在多种病理条件下上调。在这里，我们分析了 FHL2 转基因小鼠（Apo-FHL2）肝脏中 FHL2 过表达的影响。
我们首先检查了 Apo-FHL2 肝脏中的细胞增殖和细胞凋亡，并进行部分肝切除术以研究肝再生中 FHL2 的高表达。然后通过实时 PCR 分析人肝癌和相邻非肿瘤性肝脏中 FHL2 的表达。最后，使用 Apo-FHL2；Apc（lox/lox）小鼠评估 FHL2 在肝癌发生中的作用。
转基因肝脏中的细胞增殖增加了六倍，同时伴随着细胞凋亡，导致肝脏质量正常。在 Apo-FHL2 肝脏中，细胞周期蛋白 D1 和 p53 均明显增加。FHL2 结合并激活 p53 启动子，并且显性负 p53 突变体削弱了 FHL2 在肝细胞中诱导的细胞凋亡，为支持 p53 依赖性细胞死亡机制的证据提供了支持。在 Apo-FHL2 小鼠的部分肝切除术后，肝细胞显示出先进的 G1 期进入和 DNA 合成，导致肝脏重量恢复加速。有趣的是，人类肝脏标本中 FHL2 的上调与炎症评分和肝硬化的增加显著相关。最后，虽然 Apo-FHL2 小鼠没有肿瘤，但 FHL2 转基因增强了肝脏特异性缺失腺瘤性结肠息肉基因和异常 Wnt/β-catenin 信号传导在 Apc（lox/lox）动物中诱导的肝癌发生。
我们的结果表明 FHL2 参与调节增殖和细胞死亡机制的信号通路，并强调 FHL2 在肝脏稳态和癌变中的重要作用。
