低氧诱导的长链非编码RNA-HIO在原发性肝癌中的生物学意义和分子机制

Hypoxia is a common and critical hallmark for solid tumors including hepatocellular carcinoma. Long noncoding RNAs have been proved to be involved in initiation and advancement of hepatocellular carcinoma. However, the role of long noncoding RNAs in regulatory net of hypoxia microenvironment and liver cancer cells remains undefined. High throughput resource revealed that amount of long noncoding RNAs would be deregulated by hypoxia in two HCC cell lines, which suggesting the potential involvement of long noncoding RNAs leading us to explore the essential long noncoding RNAs in regulatory net between hypoxia and HCC cells. We combined the previous data of tumor related expression profiling and screened a hypoxia induced long noncoding RNA (HIO) was up-regulated in HCC when compared to nontumoral tissues. Then, in this project, we sought to investigate the functions in HCC by in vitro and in vivo experiments and explore the mechanisms underlying the aberrant expression of HIO induced by hypoxia. Finally, we would determine the clinical significance of HIO as a biomarker and therapeutic target for HCC. Together, we aimed to illustrate the role of hypoxia induced long noncoding RNAs in hepatocellular carcinoma, which would further explain the regulatory mechanisms of the interaction between hypoxia and cancer cells and supply the possibility to design hypoxia-targeted therapies by manipulation of related long noncoding RNAs.

低氧微环境是实体肿瘤包括原发性肝癌的共同特征，参与了肝癌的发生和发展，长链非编码RNA被证实为肝癌中重要调控因子，而低氧微环境与肝癌细胞调控网络中长链非编码RNA的作用仍是研究空白。通过高通量手段检测发现低氧可导致大量长链非编码RNA表达改变，我们推测在低氧微环境和肝癌细胞相互作用中存在具有重要生物学意义的长链非编码RNA。我们结合前期肝癌病人样本的表达谱数据，筛选得到受低氧诱导、肝癌相关的长链非编码RNA-HIO可能发挥重要作用，本项目拟在体内外水平揭示其生物学功能和作用机制，探讨其受低氧因素的调控机制并考察其作为治疗靶点的价值。我们以期首次阐明低氧微环境因素诱导长链非编码RNA的作用和相关的分子机制，进一步丰富人们对长链非编码RNA功能多样性的认识，对揭示肿瘤微环境和肿瘤细胞相互作用的分子调控网络有重要意义，也为长链非编码RNA作为分子诊断标志物和治疗靶点奠定基础。