Construction and analysis of a model mouse with cancer caused by oxidative stress.

电子传递系统复合体II的一个亚基细胞色素b大亚基（秀丽隐杆线虫：CYT-1；小鼠和人：SDHC）的突变可导致O_2^-产生增加，从而导致能量代谢异常和细胞凋亡。最近，具有血管化头颈部肿瘤（即副神经节瘤）遗传倾向的个体已被证明含有复合体II的几种突变之一。为了进一步探讨线粒体氧化应激在肿瘤中的作用，我们建立了SDHC基因点突变的转基因细胞系和小鼠。该细胞系中凋亡细胞较多，部分逃脱凋亡的细胞发生转化。线粒体的氧化应激导致细胞凋亡导致早衰和转化导致肿瘤发生等病理。额外的细胞凋亡是通过激活线粒体信号转导途径诱导的。诱导凋亡一方面可以增强衰老细胞中存活细胞数量的减少，抑制细胞的生长能力，另一方面也可能对具有超氧化应激的转化细胞具有抑制生长的作用。提示氧化应激通过细胞凋亡抑制肿瘤，与肿瘤良性转化密切相关。为了在哺乳动物个体水平上验证这一现象，我们构建了带有氨基酸突变的SDHC基因Tet-on/off系统的条件转基因小鼠。除脑和肌肉外，四环素对转基因基因有诱导作用。转基因小鼠对氧化应激高度敏感，有望作为氧化应激致癌模型小鼠。

A mutation in a subunit, cytochrome b large subunit (C.elegans : CYT-1 ; mouse and human : SDHC), of complex II in electron transport system, results in increasing O_2^- production and therefore lead to abnormal energy metabolism and apoptosis. Recently, individuals with an inherited propensity for vascularized head and neck tumors (i.e., paragangliomas) have been demonstrated to contain one of several mutations in complex II. To further explore the role of oxidative stress from mitochondria on cancer, we established transgenic cell line and mouse with a point mutation in the SDHC gene.There were many apoptotic cells in this cell line, and some cells that escaped from apoptosis underwent transformation. Oxidative stress from mitochondria leads to pathology such as apoptosis resulting precocious aging and also transformation resulting tumorigenesis. The supernumerary apoptosis was induced by activation of a signal transduction pathway via mitochondria. The induction of the apoptosis may enhance the reduction of a number of survived cells in aged cells suppressed cell growth ability and, on the other hand, may have an effect of growth suppression in transformed cells having hyper-oxidative stress. It is suggested that oxidative stress is deeply related with benign tumorigenic transformation by tumor suppression via the apoptosis.To verify the phenomena at a mammalian individual level, we have constructed conditional transgenic mouse with Tet-on/off system with an amino acid mutated SDHC gene. The inductions of the transgenic gene by tetracycline were found in several organs and tissues except brain and muscle. Being hyper-sensitive to oxidative stress, the transgenic mouse is anticipated as a model mouse with cancer caused by oxidative stress.