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Expression of osteopontin, a target gene of de‐regulated Wnt signaling, predicts survival in colon cancer
Author(s) -
Rohde Franziska,
Rimkus Caroline,
Friederichs Jan,
Rosenberg Robert,
Marthen Carmen,
Doll Dietrich,
Holzmann Bernhard,
Siewert JörgRüdiger,
Janssen KlausPeter
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.22868
Subject(s) - osteopontin , wnt signaling pathway , colorectal cancer , cancer research , biology , gene , signal transduction , beta catenin , gene expression , cancer , medicine , oncology , genetics , immunology
Osteopontin (OPN) is a secreted phosphoprotein, which has been reported to be associated with tumor progression in numerous solid tumors. In a previous transcriptome study on colorectal cancer, we identified the gene OPN among the most strongly up‐regulated transcripts. OPN has been suggested as a putative target of Wnt signaling, but the molecular mechanism responsible for its aberrant transcription is not fully understood. We analyzed 13 normal colon tissues, 9 adenomas, 120 primary colon tumors, and 10 liver metastases by quantitative reverse‐transcription PCR. OPN expression was strongly elevated in primary colon cancer and liver metastasis, but not in pre‐cancerous lesions and UICC stage I tumors. Multivariate analysis established OPN expression as an independent prognostic parameter for overall survival. Moreover, high OPN expression identified a subgroup of patients with bad prognosis. Next, we determined immunohistochemically a correlation of OPN expression with aberrant β‐catenin staining, which is indicative of Wnt activation. Elevated expression of OPN was significantly correlated with increased cytoplasmic and nuclear β‐catenin staining. The in vivo role of Wnt signaling for the expression of OPN was tested in genetically defined mouse models with ( Apc 1638N ) or without ( pvillin‐KRAS V12G ) Wnt activating mutations. Mutation of the tumor suppressor APC was necessary for upregulation of OPN expression in the murine tumors on transcript and on protein levels. Thus, OPN is a transcriptional target of aberrant Wnt signaling, and OPN expression alone predicts survival in human colon cancer. © 2007 Wiley‐Liss, Inc.