长链非编码RNA-HEIH通过结合HuR蛋白调控肝癌转移的分子机制

In recent years, long noncoding RNAs (lncRNAs) have been shown to have critical regulatory roles in cancer biology. In our previous study, liver samples from patients with HBV-related hepatocellular carcinoma (HCC) were analyzed for levels of a specific differentially expressed lncRNA (termed lncRNA-HEIH). The expression level of lncRNA-HEIH in HBV-related HCC is significantly associated with recurrence and is an independent prognostic factor for survival. We also found that the expression of lncRNA-HEIH in the male patient HCC tissues was higher than female patients HCC tissues. Further experiments show that lncRNA-HEIH can bind to HuR protein and promote the expression and secretion of IL- 6, IL-8, IL-1α and IL-1β. According to the literature, it seems reasonable that lncRNA-HEIH may promote those cytokines expression and secretion, resulting in the worse prognosis of male HCC patients, through binding of HuR protein. This project attempts to explore tumor cell signal transduction network regulated by lncRNA-HEIH in HCC tissue and clarify molecular mechanisms of promoting expression and secretion of IL-6, IL -8, IL-1α, IL-1β through a combination of HuR protein. Also the molecular basis of the expression of lncRNA-HEIH in the male patient HCC tissues was higher than female patient HCC tissues will be studied. Together, our objective here is to highlight the important roles of lncRNA-HEIH in the metastasis of HCC and test whether it is possible to apply lncRNA-HEIH in HCC therapy and prediction of HCC metastasis.

前期实验结果显示：长链非编码RNA-HEIH（lncRNA-HEIH）在男性病人肝癌组织中的表达量高于女性病人，并可以促进肝癌转移，特异性地结合HuR蛋白，增加IL-6、IL-8等细胞因子的表达和分泌。综合前期结果和文献信息我们认为lncRNA-HEIH可能通过结合的HuR蛋白促进了肝癌细胞炎症相关细胞因子的表达和分泌，从而导致男性肝癌病人的预后更差。因此本课题试图通过分子生物学手段及临床样本的检测与分析，对lncRNA-HEIH通过结合蛋白对肿瘤细胞信号转导网络的调控进行探讨，阐明lncRNA-HEIH通过结合HuR蛋白促进IL-6、IL-8、IL-1α、IL-1β等细胞因子分泌的分子机制，及lncRNA-HEIH在男性肝癌病人癌组织中表达量高于女性病人的原因。为lncRNA-HEIH及调控的通路作为转移性肝癌的治疗靶点及肝癌转移的预警标记物提供理论支持。

前期研究结果表明lncRNA-HEIH在肝癌组织中上调表达，进一步实验表明lncRNA-HEIH可以增强肝癌转移，并且特异性地结合HuR蛋白，可促进IL-6、IL-8等细胞因子的表达和分泌。进一步的研究发现lncRNA-HEIH可能通过增加结合HuR蛋白的NEDD8修饰，促进肝癌细胞炎症相关细胞因子IL-6、IL-8的表达和分泌，从而导致lncRNA-HEIH高表达肝癌病人的预后更差。为lncRNA-HEIH及调控的通路作为转移性肝癌的治疗靶点及肝癌转移的预警标记物等临床应用提供理论支持。