基于转录组学的裸鼹鼠和盲鼹鼠天然抗癌的分子机制研究

Malignant tumor is one of the most severe disease threatening human life and health. Due to its complexity, the pathogenesis responsible for various kinds of cancers is not yet clarified. Currently, most cancer investigations make use of human tumor tissue samples, cell lines, or model organisms such as mouse and rat. However, these approaches may miss the mechanisms for immunogenetic cancer resistance. The naked mole rat (NMR) and blind mole rat (BMR) are two sequenced subterranean rodents, which display exceptional longevity and remarkable resistance to cancer, providing perfect subjects for anti-cancer investigation. In this study, We are plan to induce tumorigenesis in fibroblast cell lines of NMR, BMR, mouse and human, using not only biological carcinogen (SV40 LT, SV40 LT & Ras, SV40 LT & Ras & hTERT), but also physical treatment (gamma rays). We will employ RNA-seq to compare the transcriptomic expression patterns of cancer-resistant rodents (NMR and BMR) and cancer-prone species (mouse and human) in cell line culture. The different transcriptomic regulation features together with their genomic factors, would offer us opportunity to identify key genes and pathways involved in tumor suppressor mechanisms, thus greatly benefit our understanding on the cancer susceptibilities. In conclusion, this study will open new avenues for cancer prevention and lifespan extension, and make it possible for us to diversify the range of standard model organisms and to include various long-lived and cancer-resistant species.

恶性肿瘤是危害人类生命健康最严重的疾病之一,由于其复杂性，目前各类癌症的机理尚未真正阐明，在未来相当长一段时间内，癌症仍将是人类健康的重大障碍。目前肿瘤研究多采用人源肿瘤组织、细胞系或小鼠动物模型等，缺乏探索肿瘤预防、免疫遗传机制的理想研究材料。裸鼹鼠和盲鼹鼠是两种已经被测定基因组的，具有长寿及抗癌特性的地下啮齿动物，为研究哺乳动物的天然抗癌机制提供了绝佳材料。本项目拟针对抗癌物种（裸鼹鼠、盲鼹鼠）及易癌物种（小鼠、人）的成纤维细胞系，分别采用生物和物理方法对各细胞系进行癌变诱导。通过对诱导前后的细胞样本进行转录组研究，结合全基因组信息，比较抗癌动物相对于小鼠和人在全基因组层面和转录调控上的差异，探讨物种间癌症敏感性差异的分子基础，鉴定裸鼹鼠和盲鼹鼠抗癌特性的关键基因和通路，阐述其潜在的抗癌分子成因，为肿瘤预防提供新思路，也为裸鼹鼠和盲鼹鼠成为肿瘤天然免疫研究的动物模型做有益探索。

裸鼹鼠（NMR）和盲鼹鼠（BMR）是两种具有天然抗癌和长寿的独特特征的地下啮齿动物。本课题对抗癌性物种（裸鼹鼠、盲鼹鼠和人类）和易感性物种（小鼠）中SV40 large T（LT）和致癌性Ras（H-Ras V12）癌基因诱导的成纤维细胞进行了全面的转录组分析。首先对四个物种的基因进行比对，共得到13276个直系同源基因；继而对癌基因诱导的细胞进行转录组测序，并使用生物信息学分析。主成分分析（PCA）和差异表达基因（DEG）分析的结果显示，抗癌物种对癌基因诱导的转录变化更具拮抗作用，涉及许多途径，包括细胞分裂、细胞粘附、细胞外基质组织和代谢过程。与其他三个物种相比，裸鼹鼠细胞对致癌性Ras基因诱导的转录变化具有更高的抵抗力，其中MAPK和PI3K途径中的关键基因，例如Erk和Akt，在裸鼹鼠细胞中被下调。综合上述结果，本研究将对如何为人们加深对抗癌机制的理解和如何通过向地下啮齿动物学习来预防癌症提供新的窗口。