双靶点抑制c-met和VEGFR2治疗高侵袭性肝细胞癌及其机制研究

Previous studies have demonstrated that anti-angiogenesis(sorafenib) therapy for hepatocellular carcinoma (HCC) may promote HCC invasion and metastasis by c-met overexpression. This indicates that VEGFR2 and c-met blockade may decrease HCC invasion and metastasis. Our previous experiments suggested that HCC patients with c-met and MMP-2 high expression are more susceptible to tumor invasion and metastasis. Furthermore, overexpression of c-met upregulates MMP-2 level and promotes HCC cell invasion and metastasis. These studies suggest that VEGFR2 and c-met blockade may decrease HCC invasion and metastasis potential via regulating MMP-2 expression. To confirm this speculation, the current study will compare the effects of XL184 and sorafenib on HCC cell proliferation, apoptosis, invasion and metastasis potential, as well as tumor proliferation, invasion and metastasis potential in nude mice HCC model. Moreover, effects of c-met inhibition/upregulation on HCC cell invasion and metastasis will be also investigated when MMP-2 is silent/upregulated by siRNA interference, respectively. The current study will facilitate to clarify the effects and mechanism of VEGFR2 and c-met blockade on hepatocellular carcinoma with high metastatic potential.

研究表明索拉非尼作为抗血管生成剂治疗肝细胞癌（肝癌）的同时，一定条件下也促进肝癌侵袭转移，此过程与c-met高表达相关。我们前期研究显示，c-met和MMP-2的高表达具有同步性，并增强肝癌侵袭转移潜能。但是c-met 与MMP-2的调控机制尚不明确，而双靶点抑制VEGFR和c-met能否同时达到抑制肝癌细胞生长和降低其侵袭转移潜能的作用也值得深入研究。 为明确靶向抑制VEGFR和c-met治疗肝癌的高效性及相关机制，本项目拟首先比较XL184(c-met/VEGFR2抑制剂)和索拉非尼(VEGFR抑制剂)对肝癌细胞增殖、凋亡、侵袭能力及肝癌裸鼠模型肿瘤生长、转移和存活时间的影响；并进一步探索在siRNA沉默/上调MMP-2表达时，增强/抑制c-met对MMP-2表达和肝癌细胞侵袭迁移能力的影响，从而明确双靶点阻断c-met和VEGFR是否通过调控MMP-2发挥降低肝癌侵袭转移潜能的作用。

靶向治疗是肝癌综合治疗中重要的组成部分。索拉非尼是目前治疗肝细胞癌(肝癌)的唯一靶向药物。临床研究表明，索拉非尼可延长晚期肝癌患者的总生存期。但是，仍有相当一部分肝癌患者在接受索拉非尼治疗的过程中，肿瘤依然发生局部侵袭或远处转移。因此，寻找新的针对肝癌侵袭转移的治疗靶点并降低肿瘤侵袭转移潜能，已成为进一步提高肝癌治疗疗效的一项重要任务。课题组前期研究显示，c-met和MMP-2的高表达具有同步性，并增强肝癌侵袭转移潜能。但是c-met 与MMP-2的调控机制尚不明确，而双靶点抑制VEGFR和c-met能否同时达到抑制肝癌细胞生长和降低其侵袭转移潜能的作用也值得深入研究。.本项目进一步明确了双靶点抑制VEGFR和c-met（卡博替尼）对c-met阳性肝癌细胞增殖、侵袭能力及肝癌裸鼠模型肿瘤生长、转移具有明显的抑制作用，并促进肝癌细胞的凋亡，进而证实其抗肿瘤疗效优于索拉非尼；并进一步明确了卡博替尼通过抑制MMP-2表达等机制抑制肝癌细胞侵袭迁移能力的作用机制。研究结果为肝癌靶向治疗新靶点的选择和疗效的提高提供了新的科学依据，也为将来进一步开展基于c-met靶点肝癌靶向治疗的临床研究提供了实验基础。