Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo Park, NY 10987, USA; Department of Geriatrics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Nelson Institute of Environmental Medicine, New York University, School of Medicine, Tuxedo Park, NY 10987, USA.
Free Radic Biol Med. 2017 Dec;113:478-486. doi: 10.1016/j.freeradbiomed.2017.10.387. Epub 2017 Oct 31.
It's well documented that over-production of reactive oxygen species (ROS) causes detrimental damages to cells. While a low level of ROS, such as HO, functions as signaling transducer and motivates cell proliferation in both cancer and non-transformed stem cells. As a double-edged sword, the direct evidence for demonstrating the function of HO in the cause of tumor is barely characterized in intact cells. In our current study, we found that targeted expression of mitochondrial catalase (mCAT), but not catalase, could significantly reduce the accumulation of HO in mouse epithelial JB6 Cl41 cells, consequently led to the cell malignant transformation and anchorage-independent cell growth. Further study revealed that this reduction of HO resulted in the translocation of nucleolin from the cytoplasm to nuclear, and maintaining the nucleolin nuclear location status, and in turn stabilizing the cox-2 mRNA and consequently leading to a COX-2 protein upregulation, as well as malignant transforming mCAT-overexpressed Cl41 cells. Collectively, our studies here provide direct experimental evidence demonstrating a novel function and molecular mechanisms of mCAT in transforming mouse Cl41 cells, and high significance insight into understanding the beneficial aspect of HO in circumventing tumor promotion and the theoretical basis for the management of HO in the clinic implementation as a chemotherapeutic strategy.
有大量文献记载，活性氧（ROS）的过度产生会对细胞造成有害损伤。而低水平的 ROS，如 1O2，作为信号转导分子，能够刺激癌症和非转化干细胞的增殖。ROS 就像一把双刃剑，其在肿瘤发生中的功能的直接证据在完整细胞中几乎无法确定。在我们目前的研究中，我们发现靶向表达线粒体过氧化氢酶（mCAT）而非过氧化氢酶，可显著减少小鼠上皮 JB6 Cl41 细胞中 1O2 的积累，从而导致细胞恶性转化和非锚定依赖性细胞生长。进一步的研究表明，这种 1O2 的减少导致核仁蛋白从细胞质向核内易位，并维持核仁蛋白的核内位置状态，进而稳定 cox-2 mRNA，从而导致 COX-2 蛋白上调以及恶性转化的 mCAT 过表达 Cl41 细胞。总之，我们的研究提供了直接的实验证据，证明了 mCAT 在转化小鼠 Cl41 细胞中的新功能和分子机制，并深入了解了 1O2 在规避肿瘤促进方面的有益方面，以及将 1O2 作为化疗策略在临床实施中的管理的理论基础。
