RASSF1A负性调节淋巴毒素β受体信号转导抑制肝细胞癌发生发展的机制研究

Chronic inflammation promotes genesis and development of hepatocellular carcinoma (HCC), however the detailed mechanisms is not fully understood yet. Our previous study suggested that the abnormal expression of Ras association domain family 1A (RASSF1A) gene was closely related with genesis and development of HCC, which could bind with lymphotoxin beta receptor (LTβR). The effects of RASSF1A overexpression on HCC cell proliferation could be inhibited by interfering the expression of LTβR in HCC cells. Therefore, we proposed a hypothesis that RASSF1A negatively regulates the signal transduction of LTβR and inhibits the process of HCC. Firstly, this study will demonstrate whether RASSF1A and LTβR can form any compound. And then the regulation role of RASSF1A and LTβR combination in LTβR activation and downstream signal will be analyzed. Furthermore, the effects of RASSF1A and LTβR combination on biological behavior of HCC cells in vitro and in vivo will be investigated. Finally, the correlation between the RASSF1A and LTβR combination and clinical pathological characteristics and prognosis of HCC will be analyzed. This study will provide basic experiments to elucidate the molecular mechanism of RASSF1A in the regulation of genesis and development of HCC, and afford new theoretical basis for the prevention and treatment of HCC.

慢性炎症在肝细胞癌（HCC）的发生发展过程中具有促进作用，但具体作用机制尚未完全明确。课题组前期研究发现：RASSF1A的表达异常与HCC的发生发展密切相关，并且能与淋巴毒素β受体（LTβR）相结合，干扰HCC细胞LTβR的表达可消除RASSF1A过表达对HCC细胞生长抑制的影响。因此，我们提出RASSF1A负性调节LTβR信号转导抑制HCC发生发展的假设。本研究将首先明确RASSF1A与LTβR能否结合形成复合物,再分析RASSF1A与LTβR结合对LTβR激活及下游信号的调节作用，接着观察RASSF1A与LTβR结合对HCC细胞体内外生物学行为的影响，最后分析RASSF1A与LTβR的结合与HCC临床病理特征和预后的相关性。本研究结果将为阐明RASSF1A调控HCC发生发展的分子机制提供实验基础，也为HCC的预防和治疗提供新的理论依据。

肝细胞癌（HCC）是一种典型的炎症相关性肿瘤，课题组前期研究结果提示RASSF1A在肝脏慢性炎症到 HCC 发生发展过程发挥重要作用，但其机制未明。通过近期的深入研究，我们发现LTβR是RASSF1A参与调控肝脏慢性炎症到HCC发生的重要媒介。LTβR在肝癌组织中表达较癌旁正常组织明显增高，并且在人的肝炎、肝硬化及肝癌的临床样本中的表达水平呈递增趋势。LTβR高表达是HCC患者不良预后的独立危险因素。LTβR可以通过激活炎癌链关键信号通路NF-κB参与调控HCC的恶性表型。机制上，RASSF1A与LTβR相互作用从而拮抗LTβR的寡聚化自激活参与调控NF-κB信号通路的激活。本项目揭示了RASSF1A在HCC炎癌链中发挥作用的机制，为肝癌的临床防治提供新的预测指标及治疗靶点。在此基础上，我们还深入研究HCC中NF-κB信号通路异常活化的原因，发现HAX-1蛋白及SNHG16/miR-605-3p/TRAF6/NF-κB正反馈环路的重要作用。