Beijing Institute of Radiation Medicine, Beijing 100850, China.
Free Radic Biol Med. 2009 Oct 1;47(7):1057-66. doi: 10.1016/j.freeradbiomed.2009.07.017. Epub 2009 Jul 17.
To gain new insight into the biological function of the human augmenter of liver regeneration (hALR) in HCC, we studied its involvement in radiation-induced damage and recovery of HCC cells. We found that hALR expression was up-regulated in both HCC tissues and multiple hepatoma cell lines and correlated significantly with increased radiation clonogenic survival after radiation treatment. Exogenous expression of hALR increased radiation resistance in SMMC-7721 cells, and the increased survival was accompanied by a decrease in apoptosis and a prolonged G(2)-M arrest after irradiation. Overexpression of ALR significantly increased the mitochondrial membrane potential, inhibited cytochrome c release, and opposed the loss of intracellular ATP levels after radiation. Moreover, knockdown of ALR by siRNA resulted in inhibition of viability in the absence of exogenously added oxidative stress and radiation sensitization in HepG2 cells. Importantly, hALR expression was very low in normal hepatocyte L02 cells, and hALR silencing had a minimal effect on L02 viability and radiation sensitivity. These results suggest that human ALR is important for hepatoma cell viability and involved in the protection of hepatoma cells against irradiation-induced damage by its association with mitochondria. Targeting hALR may be a promising novel approach to enhance the radiosensitivity of hepatoma cancers.
为了深入了解人类肝脏再生增强因子 (hALR) 在 HCC 中的生物学功能，我们研究了它在 HCC 细胞辐射损伤和恢复中的作用。我们发现，hALR 在 HCC 组织和多种肝癌细胞系中均呈上调表达，且与放疗后克隆存活增加显著相关。外源性表达 hALR 增加了 SMMC-7721 细胞的辐射抗性，并且存活增加伴随着辐射后细胞凋亡减少和 G2-M 期阻滞延长。ALR 的过表达显著增加了线粒体膜电位，抑制了细胞色素 c 的释放，并阻止了辐射后细胞内 ATP 水平的降低。此外，siRNA 敲低 ALR 可抑制 HepG2 细胞在无外加氧化应激和辐射增敏情况下的活力。重要的是，hALR 在正常肝细胞 L02 中的表达非常低，而 hALR 沉默对 L02 活力和辐射敏感性的影响很小。这些结果表明，人类 ALR 对肝癌细胞活力很重要，并通过与线粒体的结合参与保护肝癌细胞免受辐射损伤。靶向 hALR 可能是增强肝癌放射敏感性的一种有前途的新方法。
