Abstract
TMPRSS4 (Transmembrane protease serine 4) is up-regulated in a broad spectrum of cancers. However, little is known about the biological effects of TMPRSS4 on hepatocellular carcinoma (HCC) and the related mechanisms. In the present study, we found that overexpression of TMPRSS4 significantly promoted the invasion, migration, adhesion and metastasis of HCC. Further more, TMPRSS4 induced EMT of HCC, which was mediated via snail and slug as a result of Raf/MEK/ERK1/2 activation, and inhibition of ERK1/2 activation by its inhibitor was associated with reduced cell invasion and reversion of EMT. In addition, we demonstrated that TMPRSS4 remarkably suppressed the expression of RECK, an inhibitor of angiogenesis, and drastically induced tumor angiogenesis and growth. More important, in clinical HCC specimens, TMPRSS4 expression was significantly correlated with tumor staging and was inversely correlated with E-cadherin and RECKS expression. Expression of TMPRSS4 is significantly associated with HCC progression and is an independent prognostic factor for postoperative worse survival and recurrence. In conclusion, TMPRSS4 functions as a positive regulator of Raf/MEK/ERK1/2 pathway and promotes HCC progression by inducing EMT and angiogenesis. The increase of TMPRSS4 expression may be a key event for HCC progression and may be regarded as a potential prognostic marker for HCC.
Highlights
Proteases contribute to degradation of the basement membrane and extracellular matrix (ECM) and to tissue remodeling, thereby play important roles in the development and homeostasis of an organism[1]
We show that TMPRSS4 significantly promoted the invasion, migration, adhesion, metastasis of hepatocellular carcinoma (HCC) through inducing epithelial-mesenchymal transition (EMT), which was mediated via snail and slug as a result of Raf/MEK/ERK1/2 activation
Comparison of the morphology of the control cells, the Lv-GFP transfected cells and Lv-TMPRSS4 transfected cells revealed that cells transfected with TMPRSS4 altered from an epithelial cobblestone appearance to an elongated/irregular shape, suggesting an epithelial-mesenchymal transition. (Fig. 1A)
Summary
Proteases contribute to degradation of the basement membrane and extracellular matrix (ECM) and to tissue remodeling, thereby play important roles in the development and homeostasis of an organism[1]. The importance of proteases as a key player in cancer progression has been increasingly recognized Aside from their ability to degrade the ECM, facilitate invasion and metastasis, proteases are signaling molecules that modulate a great variety of other molecules by underlying pathways, form interconnected cascades, circuits and networks that may be involved in all stages of the development and progression of cancer, including growth, migration, invasion, angiogenesis and metastasis[2]. Our data demonstrates that increased expression of TMPRSS4 is significantly associated with HCC progression and a worse patient survival, and is an independent prognostic factor for postoperative recurrence. These findings provide new evidence for the involvement of TMPRSS4 in the connection between EMT and angiogenesis and identify TMPRSS4 as a potential diagnostic and prognostic marker for HCC
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