Induction of α2-antiplasmin inhibits E-cadherin processing mediated by the plasminogen activator/plasmin system, leading to suppression of progression of oral squamous cell carcinoma via upregulation of cell-cell adhesion

Abstract

The plasminogen activator/plasmin system is one of the main protease systems involved in tumor cell invasion and metastasis. Our previous study has shown that plasmin degrades E-cadherin and promotes cell dissemination by downregulation of E-cadherin-mediated cell-cell adhesion in oral squamous cell carcinoma (SCC) cells. To examine the effect of downregulation of the plasminogen activator/plasmin system by •2-antiplasmin (•2-AP) on cell-cell adhesion mediated by E-cadherin in oral SCC cells, the oral SCC cell line SCCKN was stably transfected with •2-AP cDNA. Induction of •2-AP expression led to the inhibition of the proteolysis of E-cadherin by plasminogen activator/plasmin in SCC cells, resulting in the enhancement of the cell aggregation and the suppression of the cell motility. Moreover, •2-AP also reduced the ability of SCC cells to invade type I collagen gel, and suppressed tumorigenicity in vivo. These results suggested that downregulation of the plasminogen activator/ plasmin system by •2-AP might be a potent therapeutic approach to prevent the progression of oral SCC.

The fibrinolysis inhibitor α2-antiplasmin restricts lymphatic remodelling and metastasis in a mouse model of cancer

“…Although our study is consistent with the wellknown link between the activation of VEGF-D and both the remodelling of tumour lymphatics and lymph node metastasis (Harris et al, 2011(Harris et al, , 2013, the diversity of effects of the uPA/plasmin axis means we cannot completely exclude the possibility that the effects of plasmin in our model were in part due to mechanisms not involving the proteolytic processing of VEGF-D. For example, it was previously shown that driving expression of a 2 -AP in oral squamous cell carcinoma cells led to inhibition of proteolysis of E-cadherin resulting in reduced cell motility and suppression of tumourigenicity in mice (Hayashido et al, 2007). In the tumour model, we employed here, it is possible that plasmin enhanced the motility of tumour cells, thereby facilitating their access and entry to intra-tumoural lymphatics induced by VEGF-D.…”

Candidate biomarker discovery in plasma of juvenile cod (Gadus morhua) exposed to crude North Sea oil, alkyl phenols and polycyclic aromatic hydrocarbons (PAHs)

“…Alpha-2-antiplasmin constitutes a key recognition sequence for cell adhesions (Thomas et al, 2007), and has been reported to enhance cell aggregation and suppress cell mobility (Hayashido et al, 2007). It has also been found to be involved in mammalian spermatogenesis, sperm capacitation, and fertilization, as reviewed by Liu (2007).…”

Co-expression of KLK6 and KLK10 as prognostic factors for survival in pancreatic ductal adenocarcinoma

“…Another interaction partner was pigment epitheliumderived factor (PEDF), which is the major circulating inhibitor of plasmin. With this interaction, PEDF is linked to the plasminogen activator/plasmin system, which is one of the main protease systems involved in tumour cell invasion and metastasis (Hayashido et al, 2007). Only recently PEDF was also identified as a key inhibitor of stromal vasculature in the mural pancreas.…”