GOLM1（GP73）/TLR9途径抑制癌周干扰素产生促进肝癌转移恶性潜能机制研究

It is well acknowledged that micro-environment as well as the characteristics of cancer cell itself are closely contributed to malignant phenotype in hepatocellular carcinoma (HCC).Previously, we had demonstrated that expression of GOLM1 was closely correlated with the malignant phenotype in HCC by means of a high-throughput genomic filtering technology. In-depth study, we found that GOLM1 can be used as a predictive serum marker for outcome of postoperative IFNα treatment in patients with hepatocellular carcinoma. Great significant association was found between higher levels of intratumoral GLOM1 and lower levels of peritumoral IFNs which had a significantly poorer prognosis. Based on our previous study about the protein interactions, we speculated that TLR9 may have an important role as a connected molecular between GOLM1 and the suppresed interferons (IFNs) in peritumoral hepatic tissues. So we suggest that there is a new molecular mechanism as an axis of GOLM1-TLR9-IFNs-malignant potential to take effect and we are going to carry out some researches on this functional axis as below: 1. Analyze the connection between the GOLM1, TLR9, IFNs, both structurally and functionally in HCC for the confirmation of this axis. 2. Determinate the expressions of these molecular in clinical specimens to investigate the correlation between this axis and recurrence，metastasis and poor prognosis of HCC patients. 3. Disturb this functional axis by some in vitro and in vivo assays for further validation that it can effectively predict the recurrence and serve as a potential therapeutic target in HCC.

肝癌的转移复发与微环境免疫状态和肝癌细胞自身的转移特性密切相关。我们前期通过高通量基因组学筛选技术发现，GOLM1与肝癌转移恶性潜能密切联系；GOLPH2能够抑制肝癌患者术后干扰素治疗敏感性；其在癌组织表达与癌周免疫因子干扰素α、γ密切相关。基于蛋白-蛋白相互作用分析及前期研究提示，TLR9可能是GOLM1调控肝癌免疫炎症相关恶性潜能的关键中间衔接分子，由此提出“GOLM1-TLR9-IFNs-恶性潜能”功能轴这一新的分子机制。本课题拟在前期研究基础上，进一步围绕此功能轴展开以下研究：①分析肝癌细胞中GOLM1、TLR9、IFNs在表达和功能上的联系，对此功能轴进行验证；②在肝癌临床样本中检测GOLM1、TLR9、IFNs表达，探讨此功能轴与肝癌患者转移复发及预后的关系；③通过体内、体外实验，干预此功能轴，明确其对肝癌侵袭转移及免疫治疗抵抗的影响；为肝癌转移复发提供有效的预测模型干预靶点。

肝细胞肝癌（Hepatocellular carcinoma, HCC，简称肝癌）是常见的消化道恶性肿瘤。肝癌全球每年有78.2万新发病例，74.5万死亡病例。其中，中国的新发病例数及死亡病例数均占了约50%左右。当前，手术切除仍是病人获得长期生存最有效的途径，但目前只有10%-20%肝癌病人在诊断时具有根治性治疗的机会；即使是根治性切除，其术后5年复发率仍高达60%-70%。因此，探明肝癌转移的分子机制及其关键调控环节、早期识别或预测病人转移、寻求有效的干预措施和综合治疗手段对提高肝癌治疗效果、延长病人生存具有重要意义。肝癌的转移复发与微环境免疫状态和肝癌细胞自身的转移特性密切相关。我们前期通过高通量基因组学筛选技术发现，GOLM1与肝癌转移恶性潜能密切联系；GOLPH2能够抑制肝癌患者术后干扰素治疗敏感性；其在癌组织表达与癌周免疫因子干扰素α、γ密切相关。通过本项目资助我们进一步明确GOLM1 是调控肝癌免疫相关恶性生物学潜能的重要分子，深化该研究，我们通过结合蛋白质组、转录组生物信息分析，证实TLR9可能是GOLM1 GOLM1GOLM1GOLM1参与调控肝癌免疫微环境途径的重要分子。由此分析GOLM1 / TLR9功能通路与肝癌周免疫细胞因子 (IFN-α、IFNIFNIFN-γ) 、临床病 、临床病理特征及预后相关性。为寻找肝癌的诊治靶点、寻求肝癌免疫疗新途径、验证干预有效性提供了重要的临床及实验依据。