PEG-3, a Nontransforming Cancer Progression Gene, Is a Positive Regulator of Cancer Aggressiveness and Angiogenesis

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 96; no. 26; pp. 15115 - 15120
• Main Authors: Su, Zao-Zhong, Goldstein, Neil I., Jiang, Hongping, Wang, Mei-Nai, Duigou, Gregory J., Charles S. H. Young, Fisher, Paul B.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 21.12.1999; National Acad Sciences; National Academy of Sciences; The National Academy of Sciences
• Subjects: Angiogenesis; Animals; Antigens, Differentiation; Biological Sciences; Cancer; Cell Cycle Proteins; Cell lines; Cell Transformation, Neoplastic; Disease Progression; Embryonic cells; Endothelial Growth Factors - biosynthesis; English language learners; Genes; Genetic Predisposition to Disease; Humans; Lymphokines - biosynthesis; Medical research; Messenger RNA; Mice; Mice, Nude; Neoplasm Proteins - genetics; Neoplasms - genetics; Neovascularization, Pathologic - genetics; PEG-3 gene; Phenotype; Phenotypes; Protein Phosphatase 1; Proto-Oncogene Proteins; Rats; Rodents; Tumor cell line; Tumors; vascular endothelial growth factor; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.96.26.15115

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.