Expression of osteopontin, a target gene of de-regulated Wnt signaling, predicts survival in colon cancer.
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 beta-catenin staining, which is indicative of Wnt activation. Elevated expression of OPN was significantly correlated with increased cytoplasmic and nuclear beta-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.
Rohde
Franziska
F
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Rimkus
Caroline
C
Friederichs
Jan
J
Rosenberg
Robert
R
Marthen
Carmen
C
Doll
Dietrich
D
Holzmann
Bernhard
B
Siewert
Jörg-Rüdiger
JR
Janssen
Klaus-Peter
KP
D000236:Adenoma / Q000737:chemistry / Q000401:mortality; D000368:Aged; D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics*; D003106:Colon / Q000737:chemistry; D003110:Colonic Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000401:mortality*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D006801:Humans; D008113:Liver Neoplasms / Q000737:chemistry / Q000401:mortality / Q000556:secondary; D008297:Male; D051379:Mice; D008875:Middle Aged; D009154:Mutation; D053495:Osteopontin / Q000032:analysis* / Q000235:genetics*; D011230:Precancerous Conditions / Q000737:chemistry / Q000401:mortality; D011237:Predictive Value of Tests; D011379:Prognosis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D016019:Survival Analysis; D015854:Up-Regulation; D051153:Wnt Proteins / Q000235:genetics*; D051176:beta Catenin / Q000032:analysis / Q000235:genetics
D014408:Biomarkers, Tumor; D051153:Wnt Proteins; D051176:beta Catenin; D053495:Osteopontin