ECRG2 regulates ECM degradation and uPAR/FPRL1 pathway contributing cell invasion/migration.
ECRG2 is a novel tumor suppressor gene that shows sequence similarity to KAZAL-type serine protease inhibitor. We have previously demonstrated ECRG2 inhibits migration/invasion of lung cancer PG cells. However, the mechanism by which ECRG2 performs these activities remains unknown. In this study, we found that ECRG2 inhibits proteolysis activity of uPA/plasmin and MMP2, and substantially reduces the ability of HT1080 and HCT-116 cells to invade ECM. Moreover, we demonstrated ECRG2 prevents the cleavage of uPAR, disrupts the association of sD2D3 with FPRL1, and that disruption impairs FPRL1 function. Conversely, depletion of ECRG2 not only markedly increased proteolysis activity of uPA/plasmin and MMP2 but also enhanced the association of uPAR with FPRL1, stimulated cell migration/invasion. Together, our results provide evidence that ECRG2 regulates invasion/migration partly through ECM degradation and uPA/uPAR/FPRL1 pathway, and may represent a novel therapeutic target for cancer.
Department of Anatomy, Shanxi Medical University, Taiyuan, PR China.
Xiaolong
X
Cheng
Shih-Hsin
SH
Lu
Yongping
Y
Cui
D045744:Cell Line, Tumor; D002465:Cell Movement; D005109:Extracellular Matrix; D005455:Fluorescent Antibody Technique; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D045325:HCT116 Cells; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics*; D053491:Proteinase Inhibitory Proteins, Secretory; D044042:Receptors, Formyl Peptide / Q000235:genetics / Q000378:metabolism*; D044067:Receptors, Lipoxin / Q000235:genetics / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D000074162:Serine Peptidase Inhibitors, Kazal Type; D015398:Signal Transduction / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
C105101:FPR2 protein, human; D053491:Proteinase Inhibitory Proteins, Secretory; D044042:Receptors, Formyl Peptide; D044067:Receptors, Lipoxin; D055293:Receptors, Urokinase Plasminogen Activator; C473799:SPINK7 protein, human; D000074162:Serine Peptidase Inhibitors, Kazal Type; D025521:Tumor Suppressor Proteins; D020778:Matrix Metalloproteinase 2