HMGB1影响上皮间质转化在原发性肝细胞癌侵袭、转移中的作用及其机制研究

High-mobility group box 1 (HMGB1) is a kind of cancer related inflammatory mediator. Our previous work found that, HMGB1 promoted proliferation of hepatocellular carcinoma (HCC) cells and downregulation of HMGB1 obviously inhibited the migration and invasive ability of these cells. These results suggested that HMGB1 is closely associated with migration and invasion of HCC. Epithelial to mesenchymal transition (EMT) plays important roles in the metastasis of HCC, for it make cancer cells more motile, migratory and invasive. In this study, plasmid transfection and RNAi techniques will be used to investigate effects of HMGB1 alteration to the EMT process of HCC. Further more, report gene system will also be used to reveal the molecular regulatory mechanism of HMGB1 to the process of EMT. Orthotopic transplantation tumor model with immunodeficiency SCID mouse will also be invited to observe influence of HMGB1 to the process of EMT, tumor growth and metastasis of the transplanted HepG2 cells. This study will clarify the role of HMGB1 and its related pathways in the EMT process of HCC and provide evidence for therapeutic interventions targeted HMGB1 in the prevention and interruption of HCC metastasis.

高迁移率族蛋白1（HMGB1）是一种肿瘤相关炎症因子。前期工作发现：HMGB1可以促进肝癌细胞增殖，沉默HMGB1 基因可以明显减弱肝癌细胞的侵袭、迁移能力，提示HMGB1与原发性肝细胞癌（HCC）侵袭、转移的密切相关性。上皮间质转化（EMT）因能使肿瘤细胞获得侵袭、迁移能力，而在HCC的转移中起非常重要的作用。基于此，本课题拟应用RNA干扰和质粒转染等技术，研究HMGB1表达水平的改变对肝癌细胞EMT的影响；进一步，利用报告基因系统，揭示HMGB1对EMT通路的分子调节机制；选用免疫缺陷型SCID小鼠原位移植瘤模型，观察HMGB1对HepG2细胞移植瘤EMT过程及生长、转移的影响。本研究有望阐明HMGB1对肝癌细胞EMT的作用及其相关分子机制，为以HMGB1为靶点的预防和阻断HCC转移的治疗提供依据。

高迁移率族蛋白1（HMGB1）是一种肿瘤相关炎症因子，与包括原发性肝细胞癌（HCC）在内的多种肿瘤的发生、发展密切相关。在前期已经证实HMGB1表达变化与HCC侵袭、转移能力变化密切相关的基础上，本研究进一步探讨了其分子机制。上皮间质转化（EMT）因能使肿瘤细胞获得侵袭、迁移能力，而在HCC的转移中起非常重要的作用。目前尚无HMGB1直接调控HCC细胞EMT过程的报道。本研究采用慢病毒载体构建稳定转染细胞系，报告基因系统，SCID小鼠原位移植瘤模型及其他系列成熟的细胞学和分子生物学方法，开创性地进行了相关实验。研究结果表明，HMGB1表达上调可以增强HCC细胞的侵袭和迁移能力，此过程中发生了NF-κB信号通路分子的活化和细胞EMT标志物的相应变化，相应地下调HMGB1表达效应与之相反。而荧光素酶报告基因系统和NF-κB特异性阻断剂的实验，证实了HMGB1调控HCC细胞EMT过程是NF-κB信号通路依赖的。最后选用免疫缺陷型SCID小鼠肝脏原位移植瘤模型，在体内再次证实了HMGB1对HepG2细胞移植瘤生长、转移和EMT过程的调控作用。本研究首次提出HMGB1可以通过NF-κB信号通路调节HCC细胞EMT的过程，是对HMGB1在HCC中的作用及其相关分子机制的深入探讨，为以HMGB1为靶点的预防和阻断HCC的治疗提供了依据。