Proteinase-activated receptor 2 promotes tumor cell proliferation and metastasis by inducing epithelial-mesenchymal transition and predicts poor prognosis in hepatocellular carcinoma

To clarify the role of proteinase-activated receptor 2 (PAR2) in hepatocellular carcinoma, especially in the process of metastasis. PAR2 expression levels were assessed by qRT-PCR and immunohistochemistry (IHC) in patient tissues and in hepatocellular carcinoma cell lines SMMC-7721 and HepG2. Cell p...

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Published inWorld journal of gastroenterology : WJG Vol. 24; no. 10; pp. 1120 - 1133
Main Authors Sun, Liang, Li, Pi-Bao, Yao, Yan-Fen, Xiu, Ai-Yuan, Peng, Zhi, Bai, Yu-Huan, Gao, Yan-Jing
Format Journal Article
LanguageEnglish
Published United States Baishideng Publishing Group Inc 14.03.2018
Subjects
Basic Study
Proteinase-activated receptor 2
Epithelial-mesenchymal transition
Hepatocellular carcinoma
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Abstract To clarify the role of proteinase-activated receptor 2 (PAR2) in hepatocellular carcinoma, especially in the process of metastasis. PAR2 expression levels were assessed by qRT-PCR and immunohistochemistry (IHC) in patient tissues and in hepatocellular carcinoma cell lines SMMC-7721 and HepG2. Cell proliferation and metastasis were assessed both and . Immunoblotting was carried out to monitor the levels of mitogen-activated protein kinase (MAPK) and epithelial-mesenchymal transition markers. The prognosis was significantly poorer in patients with high PAR2 levels than in those with low PAR2 levels. Patients with high PAR2 levels had advanced tumor stage ( = 0.001, chi-square test), larger tumor size ( = 0.032, chi-square test), and high microvascular invasion rate ( = 0.037, chi-square test). The proliferation and metastasis ability of SMMC-7721 and HepG2 cells was increased after PAR2 overexpression, while knockdown of PAR2 decreased the proliferation and metastasis ability of SMMC-7721 and HepG2 cells. Knockdown of PAR2 also inhibited hepatocellular carcinoma tumor cell growth and liver metastasis in nude mice. Mechanistically, PAR2 increased the proliferation ability of SMMC-7721 and HepG2 cells ERK activation. Activated ERK further promoted the epithelial-mesenchymal transition of these cells, which endowed them with enhanced migration and invasion ability. These data suggest that PAR2 plays an important role in the proliferation and metastasis of hepatocellular carcinoma. Therefore, targeting PAR2 may present a favorable target for treatment of this malignancy.
AbstractList To clarify the role of proteinase-activated receptor 2 (PAR2) in hepatocellular carcinoma, especially in the process of metastasis.AIMTo clarify the role of proteinase-activated receptor 2 (PAR2) in hepatocellular carcinoma, especially in the process of metastasis.PAR2 expression levels were assessed by qRT-PCR and immunohistochemistry (IHC) in patient tissues and in hepatocellular carcinoma cell lines SMMC-7721 and HepG2. Cell proliferation and metastasis were assessed both in vitro and in vitro. Immunoblotting was carried out to monitor the levels of mitogen-activated protein kinase (MAPK) and epithelial-mesenchymal transition markers.METHODSPAR2 expression levels were assessed by qRT-PCR and immunohistochemistry (IHC) in patient tissues and in hepatocellular carcinoma cell lines SMMC-7721 and HepG2. Cell proliferation and metastasis were assessed both in vitro and in vitro. Immunoblotting was carried out to monitor the levels of mitogen-activated protein kinase (MAPK) and epithelial-mesenchymal transition markers.The prognosis was significantly poorer in patients with high PAR2 levels than in those with low PAR2 levels. Patients with high PAR2 levels had advanced tumor stage (P = 0.001, chi-square test), larger tumor size (P = 0.032, chi-square test), and high microvascular invasion rate (P = 0.037, chi-square test). The proliferation and metastasis ability of SMMC-7721 and HepG2 cells was increased after PAR2 overexpression, while knockdown of PAR2 decreased the proliferation and metastasis ability of SMMC-7721 and HepG2 cells. Knockdown of PAR2 also inhibited hepatocellular carcinoma tumor cell growth and liver metastasis in nude mice. Mechanistically, PAR2 increased the proliferation ability of SMMC-7721 and HepG2 cells via ERK activation. Activated ERK further promoted the epithelial-mesenchymal transition of these cells, which endowed them with enhanced migration and invasion ability.RESULTSThe prognosis was significantly poorer in patients with high PAR2 levels than in those with low PAR2 levels. Patients with high PAR2 levels had advanced tumor stage (P = 0.001, chi-square test), larger tumor size (P = 0.032, chi-square test), and high microvascular invasion rate (P = 0.037, chi-square test). The proliferation and metastasis ability of SMMC-7721 and HepG2 cells was increased after PAR2 overexpression, while knockdown of PAR2 decreased the proliferation and metastasis ability of SMMC-7721 and HepG2 cells. Knockdown of PAR2 also inhibited hepatocellular carcinoma tumor cell growth and liver metastasis in nude mice. Mechanistically, PAR2 increased the proliferation ability of SMMC-7721 and HepG2 cells via ERK activation. Activated ERK further promoted the epithelial-mesenchymal transition of these cells, which endowed them with enhanced migration and invasion ability.These data suggest that PAR2 plays an important role in the proliferation and metastasis of hepatocellular carcinoma. Therefore, targeting PAR2 may present a favorable target for treatment of this malignancy.CONCLUSIONThese data suggest that PAR2 plays an important role in the proliferation and metastasis of hepatocellular carcinoma. Therefore, targeting PAR2 may present a favorable target for treatment of this malignancy.
To clarify the role of proteinase-activated receptor 2 (PAR2) in hepatocellular carcinoma, especially in the process of metastasis. PAR2 expression levels were assessed by qRT-PCR and immunohistochemistry (IHC) in patient tissues and in hepatocellular carcinoma cell lines SMMC-7721 and HepG2. Cell proliferation and metastasis were assessed both and . Immunoblotting was carried out to monitor the levels of mitogen-activated protein kinase (MAPK) and epithelial-mesenchymal transition markers. The prognosis was significantly poorer in patients with high PAR2 levels than in those with low PAR2 levels. Patients with high PAR2 levels had advanced tumor stage ( = 0.001, chi-square test), larger tumor size ( = 0.032, chi-square test), and high microvascular invasion rate ( = 0.037, chi-square test). The proliferation and metastasis ability of SMMC-7721 and HepG2 cells was increased after PAR2 overexpression, while knockdown of PAR2 decreased the proliferation and metastasis ability of SMMC-7721 and HepG2 cells. Knockdown of PAR2 also inhibited hepatocellular carcinoma tumor cell growth and liver metastasis in nude mice. Mechanistically, PAR2 increased the proliferation ability of SMMC-7721 and HepG2 cells ERK activation. Activated ERK further promoted the epithelial-mesenchymal transition of these cells, which endowed them with enhanced migration and invasion ability. These data suggest that PAR2 plays an important role in the proliferation and metastasis of hepatocellular carcinoma. Therefore, targeting PAR2 may present a favorable target for treatment of this malignancy.
Author Yao, Yan-Fen
Li, Pi-Bao
Bai, Yu-Huan
Sun, Liang
Xiu, Ai-Yuan
Peng, Zhi
Gao, Yan-Jing
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Cites_doi 10.1038/nrm3758
10.1007/s00432-016-2286-1
10.1038/nrc1098
10.1073/pnas.91.20.9208
10.1053/j.gastro.2017.02.018
10.1074/jbc.M112.439950
10.1016/j.addr.2011.02.003
10.1038/nrc3447
10.1038/ncomms8353
10.1016/j.ccr.2006.07.020
10.1111/bph.12738
10.3748/wjg.v23.i41.7415
10.1038/sj.emboj.7601213
10.1371/journal.pntd.0000479
10.1152/physrev.00028.2003
10.1007/s00428-007-0558-5
10.1053/j.gastro.2015.12.041
10.1016/j.tcm.2014.06.004
10.1016/j.jacc.2013.05.076
10.1007/s00432-010-0961-1
10.1093/carcin/bgp153
10.1186/s12943-016-0538-y
10.1016/j.ccell.2016.11.009
10.1002/ijc.30426
10.18632/oncotarget.9600
10.1200/JCO.2015.61.5724
10.1016/j.ccell.2016.03.020
10.1016/S1542-3565(05)00712-3
10.1016/j.cell.2016.06.028
10.1002/hep.27070
10.1053/j.gastro.2017.02.001
10.3748/wjg.v23.i36.6639
10.1038/cddis.2014.212
10.1182/blood-2010-06-289314
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Keywords Proteinase-activated receptor 2
Epithelial-mesenchymal transition
Hepatocellular carcinoma
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Author contributions: Sun L and Gao YJ designed the research; Sun L, Xiu AY and Peng Z performed the research; Li PB and Bai YH contributed new reagents or analytic tools; Sun L and Yao YF analyzed the data; Sun L wrote the paper.
Telephone: +86-531-86927544
Correspondence to: Yan-Jing Gao, PhD, Chief Doctor, Professor, Department of Gastroenterology, Qilu Hospital of Shandong University, No. 107, West Wenhua Road, Jinan 250012, Shandong Province, China. gaoyanjing@sdu.edu.cn
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References ref13
ref35
ref12
ref34
ref15
ref14
ref31
ref30
ref11
ref33
ref10
ref32
ref2
ref1
ref17
ref16
ref19
ref18
ref24
ref23
ref26
ref25
ref20
ref22
ref21
ref28
ref27
ref29
ref8
ref7
ref9
ref4
ref3
ref6
ref5
References_xml – ident: ref22
  doi: 10.1038/nrm3758
– ident: ref3
  doi: 10.1007/s00432-016-2286-1
– ident: ref5
  doi: 10.1038/nrc1098
– ident: ref6
  doi: 10.1073/pnas.91.20.9208
– ident: ref30
  doi: 10.1053/j.gastro.2017.02.018
– ident: ref9
  doi: 10.1074/jbc.M112.439950
– ident: ref24
  doi: 10.1016/j.addr.2011.02.003
– ident: ref23
  doi: 10.1038/nrc3447
– ident: ref29
  doi: 10.1038/ncomms8353
– ident: ref28
  doi: 10.1016/j.ccr.2006.07.020
– ident: ref34
  doi: 10.1111/bph.12738
– ident: ref2
  doi: 10.3748/wjg.v23.i41.7415
– ident: ref27
  doi: 10.1038/sj.emboj.7601213
– ident: ref8
  doi: 10.1371/journal.pntd.0000479
– ident: ref7
  doi: 10.1152/physrev.00028.2003
– ident: ref25
  doi: 10.1007/s00428-007-0558-5
– ident: ref1
  doi: 10.1053/j.gastro.2015.12.041
– ident: ref10
  doi: 10.1016/j.tcm.2014.06.004
– ident: ref11
  doi: 10.1016/j.jacc.2013.05.076
– ident: ref17
  doi: 10.1007/s00432-010-0961-1
– ident: ref13
– ident: ref16
  doi: 10.1093/carcin/bgp153
– ident: ref19
  doi: 10.1186/s12943-016-0538-y
– ident: ref32
  doi: 10.1016/j.ccell.2016.11.009
– ident: ref12
  doi: 10.1002/ijc.30426
– ident: ref14
  doi: 10.18632/oncotarget.9600
– ident: ref4
  doi: 10.1200/JCO.2015.61.5724
– ident: ref33
  doi: 10.1016/j.ccell.2016.03.020
– ident: ref26
  doi: 10.1016/S1542-3565(05)00712-3
– ident: ref21
  doi: 10.1016/j.cell.2016.06.028
– ident: ref18
  doi: 10.1002/hep.27070
– ident: ref31
  doi: 10.1053/j.gastro.2017.02.001
– ident: ref35
  doi: 10.3748/wjg.v23.i36.6639
– ident: ref20
  doi: 10.1038/cddis.2014.212
– ident: ref15
  doi: 10.1182/blood-2010-06-289314
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Snippet To clarify the role of proteinase-activated receptor 2 (PAR2) in hepatocellular carcinoma, especially in the process of metastasis. PAR2 expression levels were...
To clarify the role of proteinase-activated receptor 2 (PAR2) in hepatocellular carcinoma, especially in the process of metastasis.AIMTo clarify the role of...
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Title Proteinase-activated receptor 2 promotes tumor cell proliferation and metastasis by inducing epithelial-mesenchymal transition and predicts poor prognosis in hepatocellular carcinoma
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