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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 HE stain of TMPRSS4 overexpression tumors that metastasize to live, intestinal mesentery, spleen, mediastinu, thoracic cavity and lung; B Immunohistochemical assay of tumors in mice of the control group, Lv-GFP group and Lv-TMPRSS4 group revealed that E-cadherin expression was significantly reduced while the expression of vimentin and activity of ERK1/2 was greatly enhanced in tumors overexpressing TMPRSS4; C Positive and negative expression of TMPRSS4, E-cadherin and RECK in human HCC samples by using human tissue microarray; DBox-and-whisker plots of the staining. The immunoreactive score of human HCC (T) and adjacent nontumor tissues (N) is shown as mean ± SD.
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f4: A HE stain of TMPRSS4 overexpression tumors that metastasize to live, intestinal mesentery, spleen, mediastinu, thoracic cavity and lung; B Immunohistochemical assay of tumors in mice of the control group, Lv-GFP group and Lv-TMPRSS4 group revealed that E-cadherin expression was significantly reduced while the expression of vimentin and activity of ERK1/2 was greatly enhanced in tumors overexpressing TMPRSS4; C Positive and negative expression of TMPRSS4, E-cadherin and RECK in human HCC samples by using human tissue microarray; DBox-and-whisker plots of the staining. The immunoreactive score of human HCC (T) and adjacent nontumor tissues (N) is shown as mean ± SD.

Mentions: We next determined whether TMPRSS4 influenced the behavior of tumors in vivo. Five weeks after orthotopic inoculation of Lv-GFP or Lv-TMPRSS4 tumor tissue into the liver, some of the mice were sacrificed and metastases were evaluated by luminescence imaging system and pathological examination, the other mice were left for evaluation of survival time. As shown in Fig. 3C, the tumors of the Lv-TMPRSS4 group were significantly bigger than those of the Lv-GFP group (p < 0.01), and the survival time of mice in Lv-TMPRSS4 group was significantly shorter than that of Lv-GFP group (p < 0.01). The mice bearing Lv-GFP tumors showed small luminescence in the liver (yellow arrow, Fig. 3D) and no luminescence in the peritoneum, whereas mice bearing Lv-TMPRSS4 tumors demonstrated strong luminescence both in the liver (yellow arrow, Fig. 3D) and in the peritoneum (blue arrow, Fig. 3D), indicating that TMPRSS4 significantly promoted the metastasis of HCC tumors. Pathological examination also revealed that both abdominal and lung metastasis (blue arrow) were significantly higher in Lv-TMPRSS4 group than in Lv-GFP group (Fig. 3D, p < 0.001). The liver tumor and metastatic nodules were confirmed histologically, and mice bearing Lv-TMPRSS4 tumors exhibited increased metastasis of HCC into various organs such as intestinal mesentery, spleen, mediastinu, thoracic cavity and lung (Fig. 4A). Taken together, these results demonstrated that TMPRSS4 played a key role in driving metastasis of HCC in vivo.


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 HE stain of TMPRSS4 overexpression tumors that metastasize to live, intestinal mesentery, spleen, mediastinu, thoracic cavity and lung; B Immunohistochemical assay of tumors in mice of the control group, Lv-GFP group and Lv-TMPRSS4 group revealed that E-cadherin expression was significantly reduced while the expression of vimentin and activity of ERK1/2 was greatly enhanced in tumors overexpressing TMPRSS4; C Positive and negative expression of TMPRSS4, E-cadherin and RECK in human HCC samples by using human tissue microarray; DBox-and-whisker plots of the staining. The immunoreactive score of human HCC (T) and adjacent nontumor tissues (N) is shown as mean ± SD.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: A HE stain of TMPRSS4 overexpression tumors that metastasize to live, intestinal mesentery, spleen, mediastinu, thoracic cavity and lung; B Immunohistochemical assay of tumors in mice of the control group, Lv-GFP group and Lv-TMPRSS4 group revealed that E-cadherin expression was significantly reduced while the expression of vimentin and activity of ERK1/2 was greatly enhanced in tumors overexpressing TMPRSS4; C Positive and negative expression of TMPRSS4, E-cadherin and RECK in human HCC samples by using human tissue microarray; DBox-and-whisker plots of the staining. The immunoreactive score of human HCC (T) and adjacent nontumor tissues (N) is shown as mean ± SD.
Mentions: We next determined whether TMPRSS4 influenced the behavior of tumors in vivo. Five weeks after orthotopic inoculation of Lv-GFP or Lv-TMPRSS4 tumor tissue into the liver, some of the mice were sacrificed and metastases were evaluated by luminescence imaging system and pathological examination, the other mice were left for evaluation of survival time. As shown in Fig. 3C, the tumors of the Lv-TMPRSS4 group were significantly bigger than those of the Lv-GFP group (p < 0.01), and the survival time of mice in Lv-TMPRSS4 group was significantly shorter than that of Lv-GFP group (p < 0.01). The mice bearing Lv-GFP tumors showed small luminescence in the liver (yellow arrow, Fig. 3D) and no luminescence in the peritoneum, whereas mice bearing Lv-TMPRSS4 tumors demonstrated strong luminescence both in the liver (yellow arrow, Fig. 3D) and in the peritoneum (blue arrow, Fig. 3D), indicating that TMPRSS4 significantly promoted the metastasis of HCC tumors. Pathological examination also revealed that both abdominal and lung metastasis (blue arrow) were significantly higher in Lv-TMPRSS4 group than in Lv-GFP group (Fig. 3D, p < 0.001). The liver tumor and metastatic nodules were confirmed histologically, and mice bearing Lv-TMPRSS4 tumors exhibited increased metastasis of HCC into various organs such as intestinal mesentery, spleen, mediastinu, thoracic cavity and lung (Fig. 4A). Taken together, these results demonstrated that TMPRSS4 played a key role in driving metastasis of HCC in vivo.

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