TY - JOUR
T1 - Transcription Factor PROX1 Induces Colon Cancer Progression by Promoting the Transition from Benign to Highly Dysplastic Phenotype
AU - Petrova, Tatiana V.
AU - Nykänen, Antti
AU - Norrmén, Camilla
AU - Ivanov, Konstantin I.
AU - Andersson, Leif C.
AU - Haglund, Caj
AU - Puolakkainen, Pauli
AU - Wempe, Frank
AU - von Melchner, Harald
AU - Gradwohl, Gérard
AU - Vanharanta, Sakari
AU - Aaltonen, Lauri A.
AU - Saharinen, Juha
AU - Gentile, Massimiliano
AU - Clarke, Alan
AU - Taipale, Jussi
AU - Oliver, Guillermo
AU - Alitalo, Kari
N1 - Funding Information:
We thank Dr. Deborah Gumucio, Dr. Dietmar Zechner, Dr. Walter Birchmeier, Dr. Hans Clevers, and Dr. Marikki Laiho for DNA constructs; Nicole Johnson for advice with experimental procedures in Prox1 flox/flox mice; Dr. Tomi Makela, Dr. Ari Ristimäki, and Dr. Valerie Meniel for tissue samples; Dr. Pekka Ellonen, Dr. Aarno Palotie, and Dr. Diego Arango for microsatellite and mutation analysis; Dr. Mika Hukkanen for help with confocal microscopy; Dr. Pertti Panula, Dr. Timo Otonkoski, and Risto Kajanne for antibodies; Outi Hallikas for help with the EEL software; and Ekaterina Scherbakova for participation at the initial stages of the experiments. Gene expression profiling was carried out at Biomedicum Helsinki Gene Chip facility. We thank Alun Parsons, Tapio Tainola, Sanna Lampi, Paula Hyvärinen, Kaisa Makkonen, Minna Pajuportti, Angela Flint, and Viviane Hauer for expert technical assistance. The study was supported by the Sigrid Jusielius Foundation, Association for International Cancer Research, Finnish Academy of Sciences, Finnish Cancer Organizations, Louis Jeantet Foundation, K. Albin Johansson Foundation, the Helsinki Biomedical Graduate School, and European Union (Lymphangiogenenomics LSHG-CT-2004-503573).
PY - 2008/5/6
Y1 - 2008/5/6
N2 - The Drosophila transcription factor Prospero functions as a tumor suppressor, and it has been suggested that the human counterpart of Prospero, PROX1, acts similarly in human cancers. However, we show here that PROX1 promotes dysplasia in colonic adenomas and colorectal cancer progression. PROX1 expression marks the transition from benign colon adenoma to carcinoma in situ, and its loss inhibits growth of human colorectal tumor xenografts and intestinal adenomas in Apcmin/+ mice, while its transgenic overexpression promotes colorectal tumorigenesis. Furthermore, in intestinal tumors PROX1 is a direct and dose-dependent target of the β-catenin/TCF signaling pathway, responsible for the neoplastic transformation. Our data underscore the complexity of cancer pathogenesis and implicate PROX1 in malignant tumor progression through the regulation of cell polarity and adhesion.
AB - The Drosophila transcription factor Prospero functions as a tumor suppressor, and it has been suggested that the human counterpart of Prospero, PROX1, acts similarly in human cancers. However, we show here that PROX1 promotes dysplasia in colonic adenomas and colorectal cancer progression. PROX1 expression marks the transition from benign colon adenoma to carcinoma in situ, and its loss inhibits growth of human colorectal tumor xenografts and intestinal adenomas in Apcmin/+ mice, while its transgenic overexpression promotes colorectal tumorigenesis. Furthermore, in intestinal tumors PROX1 is a direct and dose-dependent target of the β-catenin/TCF signaling pathway, responsible for the neoplastic transformation. Our data underscore the complexity of cancer pathogenesis and implicate PROX1 in malignant tumor progression through the regulation of cell polarity and adhesion.
KW - CELLCYCLE
UR - http://www.scopus.com/inward/record.url?scp=42949112116&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=42949112116&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2008.02.020
DO - 10.1016/j.ccr.2008.02.020
M3 - Article
C2 - 18455124
AN - SCOPUS:42949112116
SN - 1535-6108
VL - 13
SP - 407
EP - 419
JO - Cancer Cell
JF - Cancer Cell
IS - 5
ER -
