Limits...
TMPRSS4 facilitates epithelial-mesenchymal transition of hepatocellular carcinoma and is a predictive marker for poor prognosis of patients after curative resection.

Wang CH, Guo ZY, Chen ZT, Zhi XT, Li DK, Dong ZR, Chen ZQ, Hu SY, Li T - Sci Rep (2015)

Bottom Line: 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 conclusion, TMPRSS4 functions as a positive regulator of Raf/MEK/ERK1/2 pathway and promotes HCC progression by inducing EMT and angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R.China [2] Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory for Carcinogenesis &Cancer Invasion, the Chinese Ministry of Education, Shanghai 200032, P.R.China.

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.

No MeSH data available.


Related in: MedlinePlus

A Closing of the wound was much faster in Lv-TMPRSS4 group than in control and Lv-GFP group; B,C The number of invading or attached cells increased several-fold over control and vector-transfected cells when TMPRSS4 was overexpressed; D Statistical analyses confirmed that cells transfected with TMPRSS4 showed significantly enhanced ability to migration, adhesion and invasion; E Compared with control and Lv-GFP group, TMPRSS4-overexpression cells displayed significantly enhanced activation of ERK1/2, together with reduced expression of E-cadherin and enhanced expression of fibronectin, vimentin, snail and slug, which can be significantly reversed by U0126, the inhibitor of ERK1/2; F After U0126 treatment, the morphologies of TMPRSS4 overexpression cells were altered from an elongated/irregular shape to an epithelial cobblestone appearance; GU0126 treatment resulted in significant suppression of cell invasion. Bars, SD. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4507176&req=5

f2: A Closing of the wound was much faster in Lv-TMPRSS4 group than in control and Lv-GFP group; B,C The number of invading or attached cells increased several-fold over control and vector-transfected cells when TMPRSS4 was overexpressed; D Statistical analyses confirmed that cells transfected with TMPRSS4 showed significantly enhanced ability to migration, adhesion and invasion; E Compared with control and Lv-GFP group, TMPRSS4-overexpression cells displayed significantly enhanced activation of ERK1/2, together with reduced expression of E-cadherin and enhanced expression of fibronectin, vimentin, snail and slug, which can be significantly reversed by U0126, the inhibitor of ERK1/2; F After U0126 treatment, the morphologies of TMPRSS4 overexpression cells were altered from an elongated/irregular shape to an epithelial cobblestone appearance; GU0126 treatment resulted in significant suppression of cell invasion. Bars, SD. *P < 0.05.

Mentions: To examine the effect of TMPRSS4 expression on the development of malignant characteristics in HCC cells, the invasion, adhesion and migration of HCC cells were evaluated. TMPRSS4 overexpression slightly inhibited the in vitro proliferation of HCC cells (Fig. 1C), but promoted the migration of HCC cells. Closing of the wound was much faster in Lv-TMPRSS4 group than in control and Lv-GFP group (Fig. 2A), and the number of invading or attached cells of Lv-TMPRSS4 group was also increased several-fold over control and Lv-GFP group (Fig. 2B–D), indicating that the invasive activity of HCC cells was correlated with TMPRSS4 expression level.


TMPRSS4 facilitates epithelial-mesenchymal transition of hepatocellular carcinoma and is a predictive marker for poor prognosis of patients after curative resection.

Wang CH, Guo ZY, Chen ZT, Zhi XT, Li DK, Dong ZR, Chen ZQ, Hu SY, Li T - Sci Rep (2015)

A Closing of the wound was much faster in Lv-TMPRSS4 group than in control and Lv-GFP group; B,C The number of invading or attached cells increased several-fold over control and vector-transfected cells when TMPRSS4 was overexpressed; D Statistical analyses confirmed that cells transfected with TMPRSS4 showed significantly enhanced ability to migration, adhesion and invasion; E Compared with control and Lv-GFP group, TMPRSS4-overexpression cells displayed significantly enhanced activation of ERK1/2, together with reduced expression of E-cadherin and enhanced expression of fibronectin, vimentin, snail and slug, which can be significantly reversed by U0126, the inhibitor of ERK1/2; F After U0126 treatment, the morphologies of TMPRSS4 overexpression cells were altered from an elongated/irregular shape to an epithelial cobblestone appearance; GU0126 treatment resulted in significant suppression of cell invasion. Bars, SD. *P < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4507176&req=5

f2: A Closing of the wound was much faster in Lv-TMPRSS4 group than in control and Lv-GFP group; B,C The number of invading or attached cells increased several-fold over control and vector-transfected cells when TMPRSS4 was overexpressed; D Statistical analyses confirmed that cells transfected with TMPRSS4 showed significantly enhanced ability to migration, adhesion and invasion; E Compared with control and Lv-GFP group, TMPRSS4-overexpression cells displayed significantly enhanced activation of ERK1/2, together with reduced expression of E-cadherin and enhanced expression of fibronectin, vimentin, snail and slug, which can be significantly reversed by U0126, the inhibitor of ERK1/2; F After U0126 treatment, the morphologies of TMPRSS4 overexpression cells were altered from an elongated/irregular shape to an epithelial cobblestone appearance; GU0126 treatment resulted in significant suppression of cell invasion. Bars, SD. *P < 0.05.
Mentions: To examine the effect of TMPRSS4 expression on the development of malignant characteristics in HCC cells, the invasion, adhesion and migration of HCC cells were evaluated. TMPRSS4 overexpression slightly inhibited the in vitro proliferation of HCC cells (Fig. 1C), but promoted the migration of HCC cells. Closing of the wound was much faster in Lv-TMPRSS4 group than in control and Lv-GFP group (Fig. 2A), and the number of invading or attached cells of Lv-TMPRSS4 group was also increased several-fold over control and Lv-GFP group (Fig. 2B–D), indicating that the invasive activity of HCC cells was correlated with TMPRSS4 expression level.

Bottom Line: 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 conclusion, TMPRSS4 functions as a positive regulator of Raf/MEK/ERK1/2 pathway and promotes HCC progression by inducing EMT and angiogenesis.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R.China [2] Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory for Carcinogenesis &Cancer Invasion, the Chinese Ministry of Education, Shanghai 200032, P.R.China.

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.

No MeSH data available.


Related in: MedlinePlus