低氧在高原和非小细胞肺癌(NSCLC)中常常出现，低氧信号通路在肿瘤发生发展各方面都起着至关重要的作用。申请人前期利用趋同进化的方法比较了327个家养哺乳动物 (高原和平原：马、绵羊、山羊、牛、猪和狗) 的全基因组序列及转录组数据，除了已知的HIF-1/2信号通路分子，还筛选得到功能未知的基因：C10orf67。前期结果显示，C10orf67参与调控低氧诱导的细胞凋亡通路，并在NSCLC细胞和组织中高表达并调节A549增殖。申请人拟：1）利用体外生化试验研究其体外功能：细胞增殖、凋亡、迁移和侵袭等；2）利用裸鼠荷瘤实验研究其体内功能；3）结合临床大样本关联性分析、蛋白质组和转录组学等方法，解析其在低氧适应及NSCLC发生发展过程中的功能及机制。该项目利用进化及肿瘤学交叉学科的研究方法，筛选低氧适应候选基因并研究其在NSCLC中的功能与机理，在肿瘤发生机理研究领域具有创新性及广泛的应用前景。

Hypoxia occurs naturally at high-altitudes and commonly in pathological conditions (e.g. tumor, like non-small cell lung cancer: NSCLC). Here, we used large-scale comparative population genomic data to reveal the genetic mechanism and species specific features underlying high-altitude adaptation of Tibetan mammals including domestic mammals (horse, sheep, goat, cattle, pig and dog), pika, zokor, antelope, yak, et al. Interestingly, many genes involved in tumorigenesis were found to evolve under selection. We uncovered multiple novel positively selected genes from the selected gene pool, like C10orf67, which are highly expressed in non-small cell lung cancer (NSCLC) tissue, and whose depletion inhibit whereas over-expression promote lung cancerous cell A549 proliferation, migration and xenograft tumor in vivo. We also identified unique amino acid mutations on different selected genes, and have found interesting hypoxia adapted (fitness) phenotypes by generating site specific Knock-In mice. Thus, adaptation of the domestic mammals to high-altitude not only provides insights into studying pattern of physiological evolution, but also searching for novel genes and potential therapeutic targets playing important roles in hypoxic tumors.