PEG-3, a nontransforming cancer progression gene, is a positive regulator of cancer aggressiveness and angiogenesis.
Cancer is a progressive disease culminating in acquisition of metastatic potential by a subset of evolving tumor cells. Generation of an adequate blood supply in tumors by production of new blood vessels, angiogenesis, is a defining element in this process. Although extensively investigated, the precise molecular events underlying tumor development, cancer progression, and angiogenesis remain unclear. Subtraction hybridization identified a genetic element, progression elevated gene-3 (PEG-3), whose expression directly correlates with cancer progression and acquisition of oncogenic potential by transformed rodent cells. We presently demonstrate that forced expression of PEG-3 in tumorigenic rodent cells, and in human cancer cells, increases their oncogenic potential in nude mice as reflected by a shorter tumor latency time and the production of larger tumors with increased vascularization. Moreover, inhibiting endogenous PEG-3 expression in progressed rodent cancer cells by stable expression of an antisense expression vector extinguishes the progressed cancer phenotype. Cancer aggressiveness of PEG-3 expressing rodent cells correlates directly with increased RNA transcription, elevated mRNA levels, and augmented secretion of vascular endothelial growth factor (VEGF). Furthermore, transient ectopic expression of PEG-3 transcriptionally activates VEGF in transformed rodent and human cancer cells. Taken together these data demonstrate that PEG-3 is a positive regulator of cancer aggressiveness, a process regulated by augmented VEGF production. These studies also support an association between expression of a single nontransforming cancer progression-inducing gene, PEG-3, and the processes of cancer aggressiveness and angiogenesis. In these contexts, PEG-3 may represent an important target molecule for developing cancer therapeutics and inhibitors of angiogenesis.
Su
Z Z
ZZ
Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, 630 West 168th Street, New York, NY 10032, USA.
Goldstein
N I
NI
Jiang
H
H
Wang
M N
MN
Duigou
G J
GJ
Young
C S
CS
Fisher
P B
PB
D000818:Animals; D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D002471:Cell Transformation, Neoplastic; D018450:Disease Progression; D016228:Endothelial Growth Factors / Q000096:biosynthesis; D020022:Genetic Predisposition to Disease; D006801:Humans; D008222:Lymphokines / Q000096:biosynthesis; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D010641:Phenotype; D054645:Protein Phosphatase 1; D011518:Proto-Oncogene Proteins; D051381:Rats; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000943:Antigens, Differentiation; D018797:Cell Cycle Proteins; D016228:Endothelial Growth Factors; D008222:Lymphokines; D009363:Neoplasm Proteins; D054645:Protein Phosphatase 1; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C489287:Ppp1r15a protein, rat; C087519:PPP1R15A protein, human; C513256:Ppp1r15a protein, mouse