Transcription factor PROX1 induces colon cancer progression by promoting the transition from benign to highly dysplastic phenotype.
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 Apc(min/+) mice, while its transgenic overexpression promotes colorectal tumorigenesis. Furthermore, in intestinal tumors PROX1 is a direct and dose-dependent target of the beta-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.
Petrova
Tatiana V
TV
Molecular and Cancer Biology Research Program, Biomedicum Helsinki, University of Helsinki, Haartmaninkatu 8, P.O.B. 63, 00014 Helsinki, Finland. tatiana.petrova@helsinki.fi
Nykänen
Antti
A
Norrmén
Camilla
C
Ivanov
Konstantin I
KI
Andersson
Leif C
LC
Haglund
Caj
C
Puolakkainen
Pauli
P
Wempe
Frank
F
von Melchner
Harald
H
Gradwohl
Gérard
G
Vanharanta
Sakari
S
Aaltonen
Lauri A
LA
Saharinen
Juha
J
Gentile
Massimiliano
M
Clarke
Alan
A
Taipale
Jussi
J
Oliver
Guillermo
G
Alitalo
Kari
K
D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D002278:Carcinoma in Situ / Q000235:genetics; D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D015179:Colorectal Neoplasms / Q000235:genetics; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D010641:Phenotype; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D051176:beta Catenin / Q000502:physiology; D000098551:Prospero-Related Homeobox 1 Protein
D018398:Homeodomain Proteins; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D000098551:Prospero-Related Homeobox 1 Protein