title: Constitutive activation of the Wnt canonical pathway in mantle cell lymphoma.
abstract: Aberrations of the Wnt canonical pathway (WCP) are known to contribute to the pathogenesis of various types of cancer. We hypothesize that these defects may exist in mantle cell lymphoma (MCL). Both the upstream and downstream aspects of WCP were examined in MCL cell lines and tumors. Using WCP-specific oligonucleotide arrays, we found that MCL highly and consistently expressed Wnt3 and Wnt10. beta-catenin, a transcriptional factor that is a downstream target of WCP, is localized to the nucleus and transcriptionally active in all 3 MCL cell lines examined. By immunohistochemistry, 33 (52%) of 64 MCL tumors showed nuclear localization of beta-catenin, which significantly correlated with the expression of the phosphorylated/inactive form of GSK3beta (p-GSK3beta; P = .011, Fisher). GSK3beta inactivation is directly linked to WCP stimulation, since addition of recombinant sFRP proteins (a naturally occurring decoy for the Wnt receptors) resulted in a significant decrease in p-GSK3beta. Down-regulation of DvL-2 (an upstream signaling protein in WCP) by siRNA or selective inhibition of beta-catenin using quercetin significantly decreased cell growth in MCL cell lines. To conclude, WCP is constitutively activated in a subset of MCL and it appears to promote tumorigenesis in MCL.
authors.affiliation: Department of Laboratory Medicine and Pathology, Cross Cancer Institute and University of Alberta, Edmonton, AB.
authors.forename: Pascal
authors.initials: P
authors.lastname: Gelebart
authors.forename: Mona
authors.initials: M
authors.lastname: Anand
authors.forename: Hanan
authors.initials: H
authors.lastname: Armanious
authors.forename: Anthea C
authors.initials: AC
authors.lastname: Peters
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dien Bard
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
mesh_terms: D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D020522:Lymphoma, Mantle-Cell / Q000209:etiology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060508:Wnt3 Protein; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: C484142:WNT10A protein, human; C555507:WNT3 protein, human; D051153:Wnt Proteins; D060508:Wnt3 Protein; D051176:beta Catenin; D038362:Glycogen Synthase Kinase 3
references.citation: Clin Cancer Res. 2004 Jan 15;10(2):615-25
references.pmid: 14760084
references.citation: Cell. 2006 Nov 3;127(3):469-80
references.pmid: 17081971
references.citation: Circulation. 2002 Dec 10;106(24):3097-103
references.pmid: 12473558
references.citation: Genes Cells. 2005 Sep;10(9):919-28
references.pmid: 16115200
references.citation: Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3118-23
references.pmid: 14973184
references.citation: J Biol Chem. 2006 Mar 31;281(13):8607-12
references.pmid: 16446366
references.citation: Bioessays. 2002 Oct;24(10):881-4
references.pmid: 12325120
references.citation: Blood. 2006 Sep 1;108(5):1668-76
references.pmid: 16645163
references.citation: Oncogene. 2006 Dec 4;25(57):7461-8
references.pmid: 17143290
references.citation: Am J Pathol. 2008 Jan;172(1):37-49
references.pmid: 18156211
references.citation: Br J Haematol. 2007 Aug;138(3):338-48
references.pmid: 17614820
references.citation: EMBO J. 1994 May 1;13(9):2124-30
references.pmid: 8187765
references.citation: Mol Pharmacol. 2001 May;59(5):1138-46
references.pmid: 11306697
references.citation: Cardiovasc Res. 2004 Sep 1;63(4):731-8
references.pmid: 15306229
references.citation: Mol Cancer Ther. 2007 Jun;6(6):1774-84
references.pmid: 17575106
references.citation: Semin Hematol. 1999 Apr;36(2):115-27
references.pmid: 10319380
references.citation: Curr Biol. 1999 Jul 1;9(13):695-8
references.pmid: 10395542
references.citation: Sci STKE. 2005 Feb 15;2005(271):cm1
references.pmid: 15713948
references.citation: Cancer Cell. 2003 Feb;3(2):185-97
references.pmid: 12620412
references.citation: Oncogene. 2006 Dec 14;25(59):7747-57
references.pmid: 16799642
references.citation: Circ Res. 2005 Jun 24;96(12):1299-306
references.pmid: 15920021
references.citation: Cancer Res. 2003 Dec 1;63(23):8226-32
references.pmid: 14678979
references.citation: J Mol Diagn. 2004 May;6(2):84-9
references.pmid: 15096562
references.citation: Biochem Biophys Res Commun. 2005 Mar 4;328(1):227-34
references.pmid: 15670774
references.citation: Proc Natl Acad Sci U S A. 2000 Apr 11;97(8):4262-6
references.pmid: 10759547
references.citation: Blood. 1996 Apr 15;87(8):3351-9
references.pmid: 8605352
references.citation: Blood. 2001 Aug 1;98(3):787-94
references.pmid: 11468180
references.citation: EMBO J. 1994 Aug 1;13(15):3487-95
references.pmid: 8062825
references.citation: Blood. 1997 Jan 1;89(1):272-80
references.pmid: 8978301
references.citation: J Cell Sci. 2007 Feb 15;120(Pt 4):586-95
references.pmid: 17244647
references.citation: Biochem Biophys Res Commun. 2007 Jun 15;357(4):1119-23
references.pmid: 17462603
references.citation: Mol Cell Biol. 2004 Jun;24(11):4757-68
references.pmid: 15143170
references.citation: Nat Cell Biol. 2003 Oct;5(10):889-94
references.pmid: 12973359
references.citation: Mod Pathol. 2006 Sep;19(9):1192-202
references.pmid: 16763612
references.citation: Arch Pathol Lab Med. 2003 Apr;127(4):424-31
references.pmid: 12683869
references.citation: Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2773-8
references.pmid: 10706620
references.citation: Int J Oncol. 2001 Nov;19(5):977-82
references.pmid: 11604997
references.citation: Curr Opin Cell Biol. 2007 Apr;19(2):150-8
references.pmid: 17306971
references.citation: Blood. 2007 Apr 15;109(8):3462-9
references.pmid: 17148581
references.citation: Oncogene. 2006 Dec 4;25(57):7482-91
references.pmid: 17143292
references.citation: Mol Cell Endocrinol. 2005 Jun 30;238(1-2):57-67
references.pmid: 15896901
references.citation: J Dent Res. 2004 Apr;83(4):327-32
references.pmid: 15044508
references.citation: EMBO Rep. 2002 Jan;3(1):63-8
references.pmid: 11751573