中国科学院昆明动物研究所机构知识库

本论文工作主要是围绕肿瘤发生发展的分子机制的解析及抗肿瘤天然小分子先导化合物的筛选展开。第一部分研究发现non-SMC condensin I complex subunit H (NCAPH)在结直肠癌组织和细胞中相对于正常组织和正常细胞高表达，敲低NCAPH之后，抑制结直肠癌细胞增殖、迁移，使细胞周期停滞在G2/M期，促进细胞凋亡，抑制裸鼠移植瘤的生长。在高表达NCAPH的结直肠癌病人中，预后和总体生存率明显比低表达病人更好，可能与高表达NCAPH使结直肠癌细胞对放化疗敏感有关。第二部分内容基于云南省丰富的天然小分子化合物资源，与中科院昆明植物所的科研人员合作，利用不同肿瘤细胞系及胶质瘤放化疗抵抗和复发的主要细胞来源：成体神经干细胞，筛选抑制肿瘤细胞活性或影响成体神经干细胞功能的先导化合物。研究结果显示，动植物来源的新颖天然化合物吲哚生物碱、多巴胺衍生物、灵芝小分子和九香虫非肽小分子能促进成体神经干细胞的增殖、分化及自我更新的能力，而新骨架化合物吲哚生物碱可能部分通过配体不依赖地非经典Wnt信号通路促进神经干细胞的增殖。进一步研究发现，该小分子不促进神经瘤细胞的增殖，相反促进其分化为神经元，具有潜在的临床转化应用的价值。博士在读期间，还以树鼩（Tupaia belangeri）为模式动物，成功建立了基底细胞癌（basal cell carcinoma，BCC）模型，利用SmoA1慢病毒感染能够建立与人类BCC病理学特征类似的树鼩BCC模型，拟用于对基底细胞癌的发生发展有更深入的研究。目前已发表文章5篇，其中以共同一作发表在Cell Death and Disease、Tetrahedron、RSC Advances、Zoology Research（已接受）各1篇，以共同作者发表在Oganic Letters、Phytochemistry上各1篇。

This dissertation are focused on the mechanistic studies of signaling pathways involved in tumorigenesis and anti-tumor leading compounds screen. We compared the tumor tissues with corresponding adjacent non-tumor tissues and found that NCAPH is highly expressed in colorectal cancer cell lines comparing with normal human colonic epithelial cells (HCoEpiC), and many NCAPH mutations existing in colon cancer patients. Depletion of NCAPH inhibits colon cancer cell proliferation, migration in vitro and xenograft tumor formation in vivo. Furthermore, NCAPH knockdown promotes cell apoptosis and cell cycle arrest at G2/M phase. Interestingly, the NCAPH high expression in tumor tissues of colon patients had a significantly better prognosis and survival rate than low expression patients, suggesting that NCAPH high expression may promote colonic cancerous cell proliferation, on the other hand, may also sensitize these cells to chemo- or radio-therapies. Collectively, these findings reveal an important role of NCAPH in colon cancer, indicating that NCAPH could be used as a new therapeutic target in future. Because of abundant natural compounds in Yunnan provience, we cooperated with researchers from Kunming Institute of Botany, Chinese Academy of Science and screened leading compounds with anti tumor activiy or enhanced neural stem cells function, by using different tumor cell lines as well as adult neural stem cells which mainly contribute to chemoradiotherapy resistance and recurrence of glioma.Here we screened natural compound library to identify new compounds which could inhibit tumor cell proliferation or promote adult neural stem cell proliferation or pluripotency. Our results showed that novel compounds from various kinds of plants and animals including indole alkaloids, dopamine derivatives, Ganoderma lucidum small molecules and Aspongopus chinensis non-peptide small molecule can promote adult neural stem cell proliferation, differentiation or self renewal ability.In addition, new skeleton compound indole alkaloids Alstoscholarisine A (ASA), the most potential compound, could promote neural stem cells proliferation at least partially through activating a ligand-independent Wnt signaling pathway. Furtherly, we found that ASA promoted neuroblastoma cells differentiation but did not affect proliferation of them, which had potential clinical applications. . During the PhD, we also used tree shrew as animal model and successfully established basal cell carcinoma (BCC) in tree shrew which is closely related to primates, bearing many physiological and biochemistry advantages over rodents by infecting the animal tail skins using lenti-viral SmoA1, an active form of Smoothened (Smo) which will constitutively activate Hh signaling pathway. This work provides a powerful animal model for dissecting BCC pathogenesis and drug discoveries in future.