脂氧素A4调控ILK信号通路抑制肝癌发生EMT及转移的分子机制研究

Recent studies show that EMT has a close relationship with the invasion and metastasis of malignant tumors, and ILK play an important role in EMT. However, the underlying mechanisms remain unclear. Our precious studies showed that LX, the so-called stop signal of inflammation had inhibitory effect on hepatocarcinoma, and could regulate ILK and inhibit EMT and the invasion and metastasis of cancer cells. Our studies will confirm the effect of LX on EMT, and the invasion and metastasis of cancer cells via ILK pathway taking hepatocarcinoma as model. In vitro experiments, we investigated the effect of LX on EMT, the expressions of ILK and downstream molecules, and the correlation between them. In vivo experiments, we investigated the effect of BML-111(the analogue of LX) on the primary tumor and metastatic tumor, and the correlation with ILK expression. In RNA interference experiments, we investigated the inhibitory effect of LX on hepatocarcinoma by silencing ILK or FPR2 to illustrate whether the anti-tumor effect of LX was ILK or FPR2-dependent. The aim is to illustrate the mechanisms of hepatocarcinoma invasion and metastasis and look for new therapy for tumor metastasis.

新近研究表明上皮间质转化（EMT)与肿瘤的侵袭转移密切相关；整合素连接激酶(ILK)在EMT过程中扮演重要角色。然而，目前其机制尚不十分清楚。我们前期工作发现脂氧素 (LX，被誉为炎症过程的刹车信号)具有抗肝癌功能，抑制ILK活化和抑制肝癌细胞EMT等。因此，推测LX可能通过调节ILK抑制肿瘤细胞发生EMT及侵袭转移。拟以肝癌为模型，明确LX通过调节ILK，影响肿瘤细胞EMT及侵袭转移。体外实验观察LX对HepG2细胞EMT的影响和该过程与ILK及下游分子表达的关系。体内实验观察脂氧素类似物（BML-111）对H22荷瘤小鼠原发瘤和转移瘤的影响及其与ILK表达变化的关系；RNA干扰实验在细胞及动物模型上观察ILK、脂氧素受体（FPR2）的缺失表达与LX抗肝癌侵袭、转移的关系，阐明LX的抗肝癌作用是否为ILK和FPR2依赖。旨在进一步揭示肝癌侵袭转移的分子机制，为肿瘤转移寻找新的治疗靶点。

新近研究表明上皮间质转化（EMT)与肿瘤的侵袭转移密切相关；整合素连接激酶(ILK)和NF-κB在EMT过程中扮演重要角色。然而，目前其机制尚不十分清楚。我们前期工作发现脂氧素 A4(Lipoxin A4，LXA4，被誉为炎症过程的刹车信号)具有抗肿瘤作用，抑制ILK活化和抑制癌细胞EMT等。我们的研究以肝癌、宫颈癌、乳腺癌为模型，明确了LXA4通过调节ILK和NF-κB，影响肿瘤细胞EMT、迁移及转移。体外实验观察到LXA4能抑制HepG2、Hela及MCF-7细胞发生EMT，并且该作用与ILK、NF-κB及下游分子表达呈负相关。体内实验观察到脂氧素类似物（BML-111）能抑制H22荷瘤小鼠原发瘤和转移瘤的生长作用与ILK、NF-κB及下游分子表达呈负相关及转移并且与ILK表达呈负相关；RNA干扰实验表明沉默ILK表达后，LXA4作用消失。因此，LX及BML-111发挥抗癌作用是通过下调ILK和NF-κB实现的。