title: CTHRC1 acts as a prognostic factor and promotes invasiveness of gastrointestinal stromal tumors by activating Wnt/PCP-Rho signaling.
abstract: Gastrointestinal stromal tumors (GISTs) are the major gastrointestinal mesenchymal tumors with a variable malignancy ranging from a curable disorder to highly malignant sarcomas. Metastasis and recurrence are the main causes of death in GIST patients. To further explore the mechanism of metastasis and to more accurately estimate the recurrence risk of GISTs after surgery, the clinical significance and functional role of collagen triple helix repeat containing-1 (CTHRC1) in GIST were investigated. We found that CTHRC1 expression was gradually elevated as the risk grade of NIH classification increased, and was closely correlated with disease-free survival and overall survival in 412 GIST patients. In vitro experiments showed that recombinant CTHRC1 protein promoted the migration and invasion capacities of primary GIST cells. A luciferase reporter assay and pull down assay demonstrated that recombinant CTHRC1 protein activated noncanonical Wnt/PCP-Rho signaling but inhibited canonical Wnt signaling. The pro-motility effect of CTHRC1 on GIST cells was reversed by using a Wnt5a neutralizing antibody and inhibitors of Rac1 or ROCK. Taken together, these data indicate that CTHRC1 may serve as a new predictor of recurrence risk and prognosis in post-operative GIST patients and may play an important role in facilitating GIST progression. Furthermore, CTHRC1 promotes GIST cell migration and invasion by activating Wnt/PCP-Rho signaling, suggesting that the CTHRC1-Wnt/PCP-Rho axis may be a new therapeutic target for interventions against GIST invasion and metastasis.
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: caohuishcn@hotmail.com.
authors.forename: Ming-Ze
authors.initials: MZ
authors.lastname: Ma
authors.affiliation: Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: zhuangchun88@163.com.
authors.forename: Chun
authors.initials: C
authors.lastname: Zhuang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: xmyang@sibs.ac.cn.
authors.forename: Xiao-Mei
authors.initials: XM
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: zzzhang16@hotmail.com.
authors.forename: Zi-Zhen
authors.initials: ZZ
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: mahong4899@126.com.
authors.forename: Hong
authors.initials: H
authors.lastname: Ma
authors.affiliation: Department of Endoscopy, Cancer hospital, and Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: wenming_zhang@163.com.
authors.forename: Wen-Ming
authors.initials: WM
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: bettyyouyou@yeah.net.
authors.forename: Haiyan
authors.initials: H
authors.lastname: You
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: wxqin@sjtu.edu.cn.
authors.forename: Wenxin
authors.initials: W
authors.lastname: Qin
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: jrgu@shsci.org.
authors.forename: Jianren
authors.initials: J
authors.lastname: Gu
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: slyang@sibs.ac.cn.
authors.forename: Shengli
authors.initials: S
authors.lastname: Yang
authors.affiliation: Department of General Surgery, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: caohuishcn@hotmail.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. Electronic address: zzhang@shsci.org.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Zhang
mesh_terms: D001549:Benzamides / Q000627:therapeutic use; D002465:Cell Movement; D016326:Extracellular Matrix Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D010879:Piperazines / Q000627:therapeutic use; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: D001549:Benzamides; C502426:CTHRC1 protein, human; D016326:Extracellular Matrix Proteins; D010879:Piperazines; D011518:Proto-Oncogene Proteins; D011743:Pyrimidines; C107953:RAC1 protein, human; C085389:WNT5A protein, human; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C066737:RHOA protein, human; D000068877:Imatinib Mesylate; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
references.citation: Curr Top Dev Biol. 2012;101:263-95
references.pmid: 23140633
references.citation: Eur J Surg Oncol. 2011 Oct;37(10):890-6
references.pmid: 21737227
references.citation: Int J Mol Med. 2011 Jan;27(1):63-9
references.pmid: 21069266
references.citation: Nat Med. 2012 Feb 19;18(3):405-12
references.pmid: 22344299
references.citation: Proc Natl Acad Sci U S A. 2012 Sep 25;109(39):E2595-604
references.pmid: 22923691
references.citation: Virchows Arch. 2001 Jan;438(1):1-12
references.pmid: 11213830
references.citation: Hum Pathol. 2002 May;33(5):459-65
references.pmid: 12094370
references.citation: Hepatology. 2010 Jul;52(1):278-90
references.pmid: 20578145
references.citation: Autoimmun Rev. 2010 Feb;9(4):207-10
references.pmid: 19683077
references.citation: Carcinogenesis. 2013 Mar;34(3):694-702
references.pmid: 23222813
references.citation: Oncol Rep. 2005 Dec;14(6):1583-8
references.pmid: 16273260
references.citation: JAMA. 2012 Mar 28;307(12):1265-72
references.pmid: 22453568
references.citation: Bioorg Med Chem Lett. 2013 Nov 1;23(21):5814-20
references.pmid: 24060489
references.citation: Methods Mol Biol. 2013;1046:359-70
references.pmid: 23868600
references.citation: Science. 2012 Oct 5;338(6103):108-13
references.pmid: 22956684
references.citation: Hum Pathol. 2008 Oct;39(10):1411-9
references.pmid: 18774375
references.citation: Cell Signal. 2013 Oct;25(10):2069-78
references.pmid: 23602936
references.citation: Cell Mol Life Sci. 2006 Jan;63(1):82-91
references.pmid: 16378244
references.citation: Med Oncol. 2013 Mar;30(1):473
references.pmid: 23359115
references.citation: PLoS One. 2012;7(5):e37990
references.pmid: 22629471
references.citation: J Korean Med Sci. 2013 Oct;28(10):1443-8
references.pmid: 24133347
references.citation: Dev Cell. 2008 Jul;15(1):23-36
references.pmid: 18606138
references.citation: Clin Cancer Res. 2004 Jul 15;10(14):4799-805
references.pmid: 15269155
references.citation: PLoS One. 2013 Oct 04;8(10):e77219
references.pmid: 24124608
references.citation: Ann Surg Oncol. 2000 Oct;7(9):705-12
references.pmid: 11034250
references.citation: J Cell Sci. 2010 Dec 1;123(Pt 23):4011-8
references.pmid: 21084561
references.citation: Zebrafish. 2009 Mar;6(1):3-8
references.pmid: 19250033
references.citation: Int J Surg Pathol. 2002 Apr;10(2):81-9
references.pmid: 12075401
references.citation: BMC Cancer. 2007 Dec 20;7:230
references.pmid: 18096058
references.citation: PLoS One. 2013 Aug 19;8(8):e73896
references.pmid: 23977394
references.citation: Pathol Res Pract. 2008;204(11):799-807
references.pmid: 18602222
references.citation: Circ Res. 2005 Feb 4;96(2):261-8
references.pmid: 15618538
references.citation: Clin Exp Metastasis. 2012 Apr;29(4):381-95
references.pmid: 22322279
references.citation: Nat Rev Mol Cell Biol. 2012 Dec;13(12):767-79
references.pmid: 23151663
references.citation: Int J Clin Exp Pathol. 2013 May 15;6(6):1038-45
references.pmid: 23696920
references.citation: Lancet. 2013 Jan 26;381(9863):295-302
references.pmid: 23177515
references.citation: Exp Cell Res. 2008 Apr 15;314(7):1540-52
references.pmid: 18316075
references.citation: PLoS One. 2013 May 17;8(5):e62951
references.pmid: 23690967
references.citation: Lancet. 2013 Sep 14;382(9896):973-83
references.pmid: 23623056
references.citation: Cancer Sci. 2012 Jul;103(7):1327-33
references.pmid: 22590977
references.citation: Science. 2013 Mar 22;339(6126):1441-5
references.pmid: 23371553
references.citation: J Am Soc Nephrol. 2005 Jul;16(7):1977-84
references.pmid: 15901767
references.citation: Cancer Res. 2013 Jun 15;73(12):3661-70
references.pmid: 23576565
references.citation: Cell. 1995 Jun 30;81(7):1159-70
references.pmid: 7600583
references.citation: F1000 Biol Rep. 2009 Jan 21;1:4
references.pmid: 20948645
references.citation: PLoS One. 2013 Jul 29;8(7):e70324
references.pmid: 23922981
references.citation: J Cell Biol. 2012 Feb 20;196(4):395-406
references.pmid: 22351925
references.citation: APMIS. 2009 Feb;117(2):73-86
references.pmid: 19239429
references.citation: Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18289-94
references.pmid: 22021442
references.citation: J Gastroenterol. 2005 Aug;40(8):775-80
references.pmid: 16143881