低氧诱导的hsa-circ_0085549靶向调控PVT1促进结直肠癌侵袭转移的作用与机制研究

Hypoxia is a common feature of solid tumors, it is also an important driver of tumor invasion and metastasis. In recent years, regulation of circular RNA expression in a variety of diseases gradually cause for concern, but the effects and mechanism of circRNAs under hypoxic tumor microenvironment is unclear. In our pilot work, we found that,circ_0085549, is specifically induced by hypoxia. Over-expression of circ_0085549 can inhibit tumor invasion and metastasis. Our preliminary study found that circ-oo85549 may be function as a miRNAs sponge by targeting miR-194 / miR-186, and consequently positively regulates the expression of its host gene PVT1. This project will use the clinical sample to analyze the correlations between circ_0085549 expression and clinicopathological features; Using molecular biology, cell lines, and mouse model to investigate molecular mechanisms underlying circ_0085549 regulating PVT1 expression, and to illuminate the roles of circ_0085549 played in hypoxia-inducible tumor invasion and metastasis. Our study will provide the basis for a new target in diagnosis and treatment of colorectal cancer.

低氧是实体瘤的普遍特征,也是肿瘤侵袭和转移的重要驱动因素。近年来环状RNA在多种疾病中引起人们关注，但其在肿瘤低氧中的作用尚不清楚。我们前期研究发现,低氧诱导表达的环状RNA circ-0085549能促进肿瘤的侵袭和转移,并上调其宿主基因PVT1的mRNA水平, 但不影响PVT1转录.鉴于circ_0085549和PVT1有miR-194/miR-186共同结合位点,我们提出假设：circ_0085549可能通过吸附miR-194/miR-186减少其对PVT1的降解，进而通过PVT1促进肿瘤侵袭和转移。本课题将利用临床样本分析circ_0085549表达与临床病理特征的关联，利用分子、细胞实验和动物模型深入研究circ_0085549调控PVT1表达的分子机制，以阐明circ_0085549和PVT1在低氧诱导肿瘤侵袭和转移中的作用与机制, 为肿瘤诊治提供新的靶点和理论依据.

本课题利用临床样本分析circ_0085549表达与临床病理特征的关联，利用分子细胞实验和动物模型发现，环状RNAcirc_0085549可能通过吸附miR-194/miR-186减少其对PVT1的降解，进而通过PVT1促进肿瘤侵袭和转移。本课题另外证实 ，circRNA3998 在肝癌患者的肝癌组织和癌栓组织中均呈高表达；circRNA3998 于体外肝癌细胞功能实验和体内脾脏-肝转移裸鼠模型实验均展现出促进肝癌侵袭转移的功能；circRNA3998 可与PCBP1蛋白结合，充当“海绵”吸附PCBP1，从而竞争性抑制PCBP1对下游靶基因CD44v6的调控作用，增加CD44v6的表达，促进肝癌的侵袭转移。本课题阐明circ_0085549和circRNA3998在低氧诱导肿瘤侵袭和转移中的作用与机制, 为肿瘤诊治提供新的靶点和理论依据.