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Downregulation of FGL 2/prothrombinase delays HCCLM 6 xenograft tumour growth and decreases tumour angiogenesis
Author(s) -
Liu Yanling,
Xu Li,
Zeng Qili,
Wang Jingli,
Wang Ming,
Xi Dong,
Wang Xiaojing,
Yang Daofeng,
Luo Xiaoping,
Ning Qin
Publication year - 2012
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/j.1478-3231.2012.02865.x
Subject(s) - angiogenesis , downregulation and upregulation , cancer research , mapk/erk pathway , gene knockdown , kinase , chemistry , biology , microbiology and biotechnology , apoptosis , biochemistry , gene
Background Fibrinogen‐like protein 2 ( FGL 2), 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 FGL 2 expression and colocalization with fibrin was examined in 15 HCC tissues. FGL 2 downregulation was performed by targeting micro RNA in a HCCLM 6 cell line in which FGL 2 was highly expressed in xenografts of nude mice. The effects of FGL 2 knockdown on tumour growth and angiogenesis were evaluated in vitro and in vivo . Cytometric bead arrays were employed to identify FGL 2‐regulated signalling pathways. Results FGL2 was overexpressed in HCC tissues and colocalized with fibrin deposition. Knockdown of FGL2 expression in HCCLM6 cells ( hFGL 2 low 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 hFGL 2 low HCCLM6 cells exhibited decreased proliferation without significant induction of apoptosis. Overexpression of FGL2 in HCCLM6 cells or addition of recombinant hFGL 2 protein induced phosphorylation of p38‐MAPK and ERK1/2 involving protease‐activated receptors (PARs).activation. Conclusions FGL 2 contributes to HCC tumour growth and angiogenesis in a thrombin‐dependent manner, and downregulation of its expression might be of therapeutic significance in HCC .