Factor VII promotes hepatocellular carcinoma progression through ERK-TSC signaling

Abstract

We previously demonstrated PAR2 starts upstreamed with tissue factor (TF) and factor VII (FVII), inhibited autophagy via mTOR signaling in HCC. However, the mechanism underlying for merging functions of PAR2 with the coagulation system in HCC progression remained unclear. The present study aimed to investigate the role of TF, FVII and PAR2 in tumor progression of HCC. The expressions of TF, FVII and PAR2 from HCC specimens were evaluated by immunohistochemical stains and western blotting. We found that the expression of FVII, but not TF and PAR2, directly related to the vascular invasion and the clinical staging. Importantly, a lower level of FVII expression was significantly associated with the longer disease-free survival. The addition of FVII but not TF induced the expression of PAR2 and phosphorylation of ERK1/2, whereas knockdown of FVII decreased PAR2 expression and ERK1/2 phosphorylation in HCC cell lines. Furthermore, levels of phosphor-TSC2 (Ser664) were increased after treatment with FVII and PAR2 agonist whereas these were significantly abolished in the presence of a potent and specific MEK/ERK inhibitor U0126. Moreover, mTOR knockdown highly reduced Hep3B migration, which could be reverted by FVII but not TF and PAR2. These results indicated that FVII/PAR2 signaling through MEK/ERK and TSC2 axis for mTOR activation has potent effects on the migration of HCC cells. In addition, FVII/PAR2 signaling elicits an mTOR-independent signaling, which promotes hepatoma cell migration in consistent with the clinical observations. Our study indicates that levels of FVII, but not TF, are associated with tumor migration and invasiveness in HCC, and provides clues that evaluation of FVII expression in HCC may be useful as a prognostic indicator in patients with HCC and may form an alternative target for further therapy.

Factor VII-Induced MicroRNA-135a Inhibits Autophagy and Is Associated with Poor Prognosis in Hepatocellular Carcinoma

“…Our previous work established a role for TF/FVII/PAR2 signaling in inhibition of autophagy and promotion of HCC tumor progression through activation of extracellular signal regulated kinase 1/2 (ERK1/2) and subsequently tuberous sclerosis 2 (TSC2)/mammalian target of rapamycin (mTOR). 21 , 22 , 23 We further showed that miR-135a expression was also dependent upon mTOR levels, as we observed decreased miR-135a in mTOR knocked-down Hep3B cells ( Figure 1 D). To corroborate the above correlations in a clinical setting, we compared FVII protein levels with miR-135a expression in HCC tissues.…”

“…Tissue factor (TF) and factor VII (FVII) negatively regulate autophagy through signaling of the protease-activated receptor PAR2, responsible for malignant progression and decreased disease-free survival in HCC. 21 , 22 , 23 …”

The Role of PAR2 in TGF-β1-Induced ERK Activation and Cell Motility

“…These data point to a complex and intimate receptor transactivation and autocrine signaling loop between TGF-β receptor/ALK5, PAR2, and EGFR in the regulation of RAS–MEK–ERK signaling. Prompted by the strong dependency of the migratory and many other TGF-β responses on PAR2 expression on the one hand [ 24 ], and on ERK activation on the other hand [ 9 ] in conjunction with the crucial role of ERK in PAR2-stimulated cell migration [ 21 , 22 , 23 , 30 , 31 ], we set out to test, mainly in PDAC-derived cells, whether recombinant human (rh)TGF-β1-triggered ERK activation depends on endogenous PAR2.…”

Tumor microenvironment mediated by suppression of autophagic flux drives liver malignancy

“…Tumor-associated inflammation especially procoagulant-driven inflammation is now widely recognized as one of key determinants of various type of cancer [27] , [28] , [29] , [30] , including HCC [31] , [32] , [33] . The transmembrane tissue factor (TF) triggers downstream signaling upon binding with blood coagulation factor VII (FVII) and transmitting signals through protease-activated receptors (PARs) activation, especially PAR2 [34] , [35] , [36] .…”

“…A recent study also demonstrates that circular and local regional TF is overexpressed in HCC patients, and it is closely related to the invasive and metastasis indexes [52] . Our recent studies have demonstrated that activation of the TF/FVII/PAR2 axis is associated with increased migration and invasiveness in hepatoma cells in vitro [32] , [33] , [52] . This finding could be consistently observed in tumor tissues from HCC patients, where we found that increased FVII and PAR2 levels were significantly associated with clinical stage, increased invasion, and poor disease-free survival, however none of any significant association with TF expression.…”