HIF-1α－UPK1A-AS1－UPK1A正反馈环路对肝癌发生发展的影响及机制

我们已发现长链非编码RNA（lncRNA）在肝癌发生发展中发挥重要的调控功能(Gastroenterology，2015)。预实验结果表明：lncRNA UPK1A-AS1和其正义链UPK1A均受HIF-1α调控，二者又可以调控HIF-1α表达，并且三者在肝癌中的表达呈正相关关系；UPK1A-AS1促进肝癌细胞增殖和细胞糖酵解代谢，其在肝癌组织中高表达与患者不良预后相关。基于前期研究结果，我们提出HIF-1α、UPK1A-AS1、UPK1A三者形成正反馈环路促进肝癌发生发展的科学假说。为验证假说，本项目拟首先利用临床多中心大样本探讨三者在肝癌中的表达，并探讨它们与肝癌发生发展及预后的关系；其次通过肿瘤体内外实验探讨它们的生物学功能及对肿瘤代谢的影响；最后深入探讨三者之间互为调控的关系。据此，阐明HIF-1α-UPK1A-AS1-UPK1A环路在肝癌中确切的生物学功能及机制。

We have demonstrated that long noncoding RNAs (lncRNA) play an important role in initiation and progression of hepatocellular carcinoma (HCC) (Gastroenterology，2015). Recently, our preliminary data showed that lncRNA UPK1A-AS1 and its sense strand UPK1A were regulated by HIF-1α, while HIF-1α was regulated by UPK1A-AS1 and UPK1A. The positive correlation among HIF-1α, UPK1A-AS1, and UPK1A were found in HCC. UPK1A-AS1 was highly expressed in HCC tissues compared with non-tumor tissues and was associated with shorter overall survival of HCC patients. Ectopic expression of UPK1A-AS1 in HCC cells promoted cell proliferation and glycolysis. Thus, based on our data, we proposed that HIF-1α, UPK1A-AS1, and UPK1A may form a positive feedback to promote HCC initiation and progression. To confirm the hypothesis, firstly, the expression and clinical significance of HIF-1α, UPK1A-AS1, and UPK1A will be identified by clinical multicenter HCC sample. Secondly, biological functions of HIF-1α, UPK1A-AS1, and UPK1A will be investigated by in vitro and in vivo tumor assays. Lastly, we will explore regulatory interrelation among HIF-1α, UPK1A-AS1, and UPK1A and provide a framework for understanding the functional properties of these important targets. In conclusion, HIF-1α, UPK1A-AS1, and UPK1A may act as biomarkers for poor prognosis in HCC and confer a malignant phenotype to tumor cells. The positive feedback of HIF-1α-UPK1A-AS1-UPK1A may contribute to a better understanding of liver carcinogenesis and tumor progression.