The role of Fibrinogen-like proteins in Cancer

Abstract

Fibrinogen-associated protein (FREP) family is a family of proteins with a fibrin domain at the carboxyl terminus. Recent investigations illustrated that two members of FREP family, fibrinogen-like protein-1 (FGL1) and fibrinogen-like protein-2 (FGL2), play crucial roles in cancer by regulating the proliferation, invasion, and migration of tumor cells, or regulating the functions of immune cells in tumor microenvironment. Meanwhile, they are potential targets for medical intervention of tumor development. In this review, we discussed the structure, and the roles of FGL1 and FGL2 in tumors, especially the roles in regulating immune cell functions.

Keywords: Cancer; FGF1; FGF2.

Figure 1

Molecular structure of FGL2. The FGL2 gene contains two exons, which were separated by an intron. The mFGL2 contains the membrane, transmembrane, and extramembrane regions, while sFGL2 only has the extracellular domain. The amino terminal in the FGL2 gene structure is located inside of the membrane, and the carboxyl terminal is located outside of the membrane. mFGL2 is mainly secreted by macrophages, endothelial cells, and T cells, while sFGL2 is secreted by CD4⁺ T cells, CD8⁺ T cells, and Tregs.

Figure 2

The primary roles of sFGL2. sFGL2 inhibited macrophages by binding with FcγRIIB receptor to release MCP-1 to attenuate c-Jun N-terminal kinase activation. TNF-α and IFN-γ motivate sFGL2 through MAPK signaling to promote renal allograft rejection. sFGL2 inhibits the expression of MHCII, CD40, CD80, CD86 and CD83 and phosphorylation of Akt, NFκB, cAMP response element binding protein (CREB) and p38 in BMDC and reinforce the burden of tumor.

Figure 3

FGL1-involved signaling pathways. A) FGL1 is normally released by the liver in low levels but by cancer in high levels. FGL1 is identified as a major ligand for the inhibitory receptor LAG-3, and its blockade can potentiate anti-tumor T cell responses. B) FGL1 inhibits liver cancer cell proliferation by suppressing Akt signaling. C) The expression of FGL1 is down-regulated through Oxysophocarpine, which suppresses IL-6-mediated JAK2/STAT3 signal activation and subsequently strengthen the effects of anti-LAG-3 immunotherapy. D) FGL1 promotes NSCLC by regulating the PARP1/ Caspase 3 pathway.

Figure 4

FGL2-related signaling pathways in tumors. By regulating a series of signaling pathways, FGL2 promotes the apoptosis of tumor cells, and inhibits dendritic cells to promote tumor progression.