title: Activation of WNT/β-Catenin Signaling Enhances Pancreatic Cancer Development and the Malignant Potential Via Up-regulation of Cyr61.
abstract: Pancreatic ductal adenocarcinoma (PDAC), a poor prognostic cancer, commonly develops following activating mutations in the KRAS oncogene. Activation of WNT signaling is also commonly observed in PDAC. To ascertain the impact of postnatal activation of WNT-stimulated signaling pathways in PDAC development, we combined the Elastase-tva-based RCAS-TVA pancreatic cancer model with the established LSL-KrasG12D, Ptf1a-cre model. Delivery of RCAS viruses encoding β-cateninS37Aand WNT1 stimulated the progression of premalignant pancreatic intraepithelial neoplasias (PanIN) and PDAC development. Moreover, mice injected with RCAS-β-cateninS37Aor RCAS-Wnt1 had reduced survival relative to RCAS-GFP-injected controls (P<.05). Ectopic expression of active β-catenin, or its DNA-binding partner TCF4, enhanced transformation associated phenotypes in PDAC cells. In contrast, these phenotypes were significantly impaired by the introduction of ICAT, an inhibitor of the β-catenin/TCF4 interaction. By gene expression profiling, we identified Cyr61 as a target molecule of the WNT/β-catenin signaling pathway in pancreatic cancer cells. Nuclear β-catenin and CYR61 expression were predominantly detected in moderately to poorly differentiated murine and human PDAC. Indeed, nuclear β-catenin- and CYR61-positive PDAC patients demonstrated poor prognosis (P<.01). Knockdown of CYR61 in a β-catenin-activated pancreatic cancer cell line reduced soft agar, migration and invasion activity. Together, these data suggest that the WNT/β-catenin signaling pathway enhances pancreatic cancer development and malignancy in part via up-regulation of CYR61.
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605; Division of Pathology, Department of Pathology and Microbiology, Tokyo, 173-8610, Japan. Electronic address: Msano921@hotmail.com.
authors.forename: Makoto
authors.initials: M
authors.lastname: Sano
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605.
authors.forename: David R
authors.initials: DR
authors.lastname: Driscoll
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605.
authors.forename: Wilfredo E
authors.initials: WE
authors.lastname: DeJesus-Monge
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605.
authors.forename: Brian
authors.initials: B
authors.lastname: Quattrochi
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605.
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Appleman
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605.
authors.forename: Jianhong
authors.initials: J
authors.lastname: Ou
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605.
authors.forename: Lihua Julie
authors.initials: LJ
authors.lastname: Zhu
authors.affiliation: Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, 173-8610, Japan.
authors.forename: Nao
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, 173-8610, Japan.
authors.forename: Shintaro
authors.initials: S
authors.lastname: Yamazaki
authors.affiliation: Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, 173-8610, Japan.
authors.forename: Tadatoshi
authors.initials: T
authors.lastname: Takayama
authors.affiliation: Division of Pathology, Department of Pathology and Microbiology, Tokyo, 173-8610, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Sugitani
authors.affiliation: Division of Pathology, Department of Pathology and Microbiology, Tokyo, 173-8610, Japan.
authors.forename: Norimichi
authors.initials: N
authors.lastname: Nemoto
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, 10021.
authors.forename: David S
authors.initials: DS
authors.lastname: Klimstra
authors.affiliation: Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA, 01605; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, MA, 01605; Cancer Center, University of Massachusetts Medical School, Worcester, MA, 01605. Electronic address: Brian.Lewis@umassmed.edu.
authors.forename: Brian C
authors.initials: BC
authors.lastname: Lewis
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D055515:Cysteine-Rich Protein 61 / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D015870:Gene Expression; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D018874:Spheroids, Cellular; D059467:Transcriptome; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D055515:Cysteine-Rich Protein 61; D051153:Wnt Proteins; D051176:beta Catenin