肝癌特异性Linc-GALH对靶基因Gankyrin的调控及其影响肝癌转移的机制研究

Hepatocellular carcinoma (HCC) by means of its highly invasive and metastatic biological characteristics became the main disease affecting the treatment efficacy and long-term survival of patients in China. .By using the multi-genealogy specimen and high throughput sequencing technology, we have screened out two tumor metastasis related molecules which are Gankyrin and Gankyrin associated LincRNA in Hepatocellular carcinoma, named as Linc-GALH. We found that Linc-GALH could significantly upregulated Gankyrin expression and augmented HCC cell line invasion via its regulation on transmethylase..Since the exact mechanism that Linc-GALH regulating Gankyrin and its impact on HCC metastasis are unclear, in this study, large scale analysis of HCC specimen will be involved to determine the correlation between Linc-GALH/Gankyrin and HCC metastasis. Various models will be established to verify the mechanism of Linc-GALH affecting Gankyrin activity. At the same time, the molecular basis underlying the Gankyrin associated metastasis will be investigated. Moreover, degradation products deriving from Linc-GALH will be analyzed in the peripheral blood and its potential of early-predicting HCC metastasis will be explored..In conclusion, clarification of the mechanism underlying Linc-GALH induced HCC metastasis will be benefit for better understand HCC progression and lying theoretical basis for developing novel predicting markers and treatment targets.

肝癌作为威胁我国人民健康的重大疾病，其高侵袭性、高转移性是影响疗效和患者长期生存的主要原因。通过多谱系、多人群标本的高通量测序，我们筛选出与肝癌转移密切相关的Gankyrin基因及与之调控相关的肝癌特异性长链非编码RNA，Linc-GALH。初步研究提示，Linc-GALH可能通过调控甲基转移酶活性降低Gankyrin基因甲基化水平，使之表达上调，并促进肝癌细胞侵袭。但目前对于Linc-GALH功能的研究尚未见诸报道。因此，本项目拟利用大量临床标本验证Linc-GALH对其靶基因Gankyrin的调控机制，并揭示其与肝癌转移的关系。同时，本研究也将筛选循环中Linc-GALH的稳定降解产物并探讨其作为预测肝癌转移早期指标的可能性。综上，本项目旨在进一步阐明肝癌发生转移的分子机制，筛选早期预测肝癌转移的标记物，也为寻找新的治疗靶点提供依据。

肝细胞肝癌是导致癌症相关死亡的重要原因。尽管肝癌的早期诊断及治疗手段已取得了进展，但是早期诊断绿和长期生存率依然很低。 肝细胞性肝癌细胞的迁徙、侵袭能力和频发的术后复发的原因仍未完全阐明。 长链非编码RNA（lncRNAs）是一类长度大于200nt，且无法编码蛋白的转录本。 研究证明许多lncRNAs在调节癌基因和抑癌基因的表达方面有重要作用，并参与包括肝癌在内的多种肿瘤的发生发展过程。 在此研究中，我们发现一种lincRNA的表达与Gankyrin的表达一致，将其命名为肝细胞性肝癌中Gankyrin相关LincRNA (Linc-GALH)。并且发现Linc-GALH可通过调节Gankyrin的甲基化状态，从而调节Gankyrin的表达进而调控肝癌细胞的增殖，侵袭以及转移。