Downregulation of FGL2/prothrombinase delays HCCLM6 xenograft tumour growth and decreases tumour angiogenesis

Liver Int. 2012 Nov;32(10):1585-95. doi: 10.1111/j.1478-3231.2012.02865.x. Epub 2012 Aug 24.


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 (hFGL2(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 hFGL2(low) 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / metabolism*
  • Cell Line, Tumor
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Fibrin / metabolism
  • Fibrinogen / metabolism*
  • Flow Cytometry
  • Gene Expression Regulation, Neoplastic / physiology*
  • Gene Knockdown Techniques
  • Humans
  • Immunohistochemistry
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Liver Neoplasms / metabolism*
  • Mice
  • Mice, Nude
  • MicroRNAs / metabolism
  • Neovascularization, Pathologic / metabolism
  • Neovascularization, Pathologic / physiopathology*
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Thromboplastin


  • FGL2 protein, human
  • MicroRNAs
  • Fibrin
  • Fibrinogen
  • Thromboplastin
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases