title: TMPRSS4 facilitates epithelial-mesenchymal transition of hepatocellular carcinoma and is a predictive marker for poor prognosis of patients after curative resection.
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.
authors.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.
authors.forename: Cheng-Hao
authors.initials: CH
authors.lastname: Wang
authors.affiliation: Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R.China.
authors.forename: Zhong-Yi
authors.initials: ZY
authors.lastname: Guo
authors.affiliation: Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R.China.
authors.forename: Ze-Ting
authors.initials: ZT
authors.lastname: Chen
authors.affiliation: Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R.China.
authors.forename: Xu-Ting
authors.initials: XT
authors.lastname: Zhi
authors.affiliation: Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R.China.
authors.forename: Deng-Ke
authors.initials: DK
authors.lastname: Li
authors.affiliation: Liver Cancer Institute and Zhongshan Hospital, Fudan University, Key Laboratory for Carcinogenesis &Cancer Invasion, the Chinese Ministry of Education, Shanghai 200032, P.R.China.
authors.forename: Zhao-Ru
authors.initials: ZR
authors.lastname: Dong
authors.affiliation: Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R.China.
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Chen
authors.affiliation: Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R.China.
authors.forename: San-Yuan
authors.initials: SY
authors.lastname: Hu
authors.affiliation: Department of general surgery, Qilu Hospital, Shandong University, Jinan 250012, P.R.China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D002448:Cell Adhesion / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D058851:GPI-Linked Proteins / Q000235:genetics; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology* / Q000601:surgery; D020935:MAP Kinase Signaling System; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000235:genetics; D011379:Prognosis; D012307:Risk Factors; D012697:Serine Endopeptidases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation; D048490:raf Kinases / Q000378:metabolism
chemical_list: D015820:Cadherins; D058851:GPI-Linked Proteins; D008565:Membrane Proteins; C115460:RECK protein, human; D048490:raf Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D012697:Serine Endopeptidases; C528837:TMPRSS4 protein, human