Downregulation of FGL2/prothrombinase delays HCCLM6 xenograft tumour growth and decreases tumour angiogenesis
Downregulation of FGL2/prothrombinase delays HCCLM6 xenograft tumour growth and decreases tumour angiogenesis
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FGL2/凝血酶原酶的下调可延迟 HCCLM6 异种移植肿瘤的生长并减少肿瘤血管生成
DOI：
10.1111/j.1478-3231.2012.02865.x
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发表时间：
2012-11-01
影响因子：
6.7
通讯作者：
Ning, Qin
中科院分区：
文献类型：
--
作者：
Liu, Yanling;Xu, Li;Ning, Qin
纤维蛋白原样蛋白2（FGL 2），它直接从凝血酶原产生凝血酶，而不激活传统的凝血级联反应，被证明是在各种人类恶性肿瘤中过表达。本研究旨在探讨其在肝细胞癌（HCC）中的表达模式、生物学功能及其作用机制。方法检测15例肝癌组织中FGL 2的表达及与纤维蛋白的共定位。通过靶向HCCLM 6细胞系中的微小RNA来进行FGL 2下调，其中FGL 2在裸鼠的异种移植物中高度表达。在体外和体内评估FGL 2敲低对肿瘤生长和血管生成的影响。采用流式细胞仪珠阵列来鉴定FGL 2调节的信号传导途径。结果FGL 2在肝癌组织中高表达，并与纤维蛋白沉积共定位。HCCLM 6细胞中FGL 2表达的敲低（hFGL 2low HCCLM 6）导致异种移植物肿瘤生长在42天的观察期内延迟，并且血管形成减少，这伴随着细胞外信号调节激酶（ERK）和c-Jun N-末端激酶（JNK）的磷酸化减少。hFGL 2low HCCLM 6细胞在体外表现出增殖下降，但没有显著诱导凋亡。在HCCLM 6细胞中过表达FGL 2或加入重组hFGL 2蛋白诱导p38-MAPK和ERK 1/2磷酸化，涉及蛋白酶激活受体（PARs）激活。结论FGL 2以凝血酶依赖的方式参与肝癌的生长和血管生成，下调其表达可能对肝癌的治疗具有重要意义。
Background Fibrinogen-like protein 2 (FGL2), which directly generates thrombin from prothrombin without activation of the conventional coagulation cascade, was shown to be overexpressed in various human malignant tumours. Aims Herein, we aimed to investigate its expression pattern, biological function and mechanism of action in hepatocellular carcinoma (HCC). Methods FGL2 expression and colocalization with fibrin was examined in 15 HCC tissues. FGL2 downregulation was performed by targeting microRNA in a HCCLM6 cell line in which FGL2 was highly expressed in xenografts of nude mice. The effects of FGL2 knockdown on tumour growth and angiogenesis were evaluated in vitro and in vivo. Cytometric bead arrays were employed to identify FGL2-regulated signalling pathways. Results FGL2 was overexpressed in HCC tissues and colocalized with fibrin deposition. Knockdown of FGL2 expression in HCCLM6 cells (hFGL2low HCCLM6) resulted in delayed xenografts tumour growth within an observation period of 42 days and decreased vascularization, which was accompanied by decreased phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N-terminal kinase (JNK). In vitro hFGL2low HCCLM6 cells exhibited decreased proliferation without significant induction of apoptosis. Overexpression of FGL2 in HCCLM6 cells or addition of recombinant hFGL2 protein induced phosphorylation of p38-MAPK and ERK1/2 involving protease-activated receptors (PARs).activation. Conclusions FGL2 contributes to HCC tumour growth and angiogenesis in a thrombin-dependent manner, and downregulation of its expression might be of therapeutic significance in HCC.