PEG-3, a nontransforming cancer progression gene, is a positive regulator of cancer aggressiveness and angiogenesis

Abstract

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 ( 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.

Cooperation between AP1 and PEA3 sites within the progression elevated gene-3 (PEG-3) promoter regulate basal and differential expression of PEG-3 during progression of the oncogenic phenotype in transformed rat embryo cells

“…To evaluate the relationship between PEG-3 expression and transformation progression we have used a series of rodent cell lines that span the gamut from normal to highly progressed (Fisher et al, 1978;Babiss et al, 1985;Duigou et al, 1989;Reddy et al, 1993;Su et al, 1997Su et al, , 1999. A hallmark of the progression phenotype in this rodent model is the ability to grow with enhanced e ciency in an anchorage-independent manner and to induce tumors in nude mice with a reduced tumor latency time (18 ± 21 days as opposed to 38 ± 44 days, respectively) (Babiss et al, 1985;Su et al, 1999).…”

“…Experimental evidence indicates that a number of diverse acting genetic elements can contribute to cancer development and transformation progression (Fisher, 1984;Bishop, 1991;Liotta et al, 1991;Knudson, 1993;Levine, 1993;Hartwell and Kastan, 1994;Kang et al, 1998a;Vogelstein and Kinzler, 1993;Su et al, 1997Su et al, , 1999. Important target genes involved in these processes include, oncogenes, tumor suppressor genes and genes regulating genomic stability, cancer aggressiveness and angiogenesis (Fisher, 1984;Bishop, 1991;Liotta et al, 1991;Knudson, 1993;Levine, 1993;Hartwell and Kastan, 1994;Kang et al, 1998a;Vogelstein and Kinzler, 1993;Su et al, 1997Su et al, , 1999. Recently, several novel genetic elements have been identi®ed that associate with or in speci®c instances directly regulate cancer aggressiveness, i.e., progression elevated (PEGen) and progression suppressed (PSGen) genes (Kang et al, 1998a;Su et al, 1997Su et al, , 1999).…”

“…Important target genes involved in these processes include, oncogenes, tumor suppressor genes and genes regulating genomic stability, cancer aggressiveness and angiogenesis (Fisher, 1984;Bishop, 1991;Liotta et al, 1991;Knudson, 1993;Levine, 1993;Hartwell and Kastan, 1994;Kang et al, 1998a;Vogelstein and Kinzler, 1993;Su et al, 1997Su et al, , 1999. Recently, several novel genetic elements have been identi®ed that associate with or in speci®c instances directly regulate cancer aggressiveness, i.e., progression elevated (PEGen) and progression suppressed (PSGen) genes (Kang et al, 1998a;Su et al, 1997Su et al, , 1999). The precise mechanism by which these di erent genes orchestrate the complex process of cancer progression represent an important area of investigation with potential for de®ning novel pathways and target molecules that could lead to new diagnostic and therapeutic approaches for cancer.…”

A cancer terminator virus eradicates both primary and distant human melanomas

“…21,[39][40][41] The PEG-3 gene was cloned using subtraction hybridization as an upregulated transcript from a transformation progression rodent cancer model. 42,43 Of direct relevance for gene therapy applications, activity of the PEG-3 promoter (PEG-Prom) is significantly and often markedly elevated not only in rodent but also in human cancer cells of diverse origin when compared to normal cells. 21,[39][40][41] The mechanism underlying the cancer-specific expression of the PEG-Prom implicates two transcription factors, AP-1 and PEA-3, which are expressed at elevated levels, either singly or in combination, in virtually all types of cancers.…”

“…21,[39][40][41] The mechanism underlying the cancer-specific expression of the PEG-Prom implicates two transcription factors, AP-1 and PEA-3, which are expressed at elevated levels, either singly or in combination, in virtually all types of cancers. 21,[39][40][41][42][43][44][45] Using the PEG-Prom to transcriptionally regulate green fluorescence protein (GFP) or luciferase gene expression via a replication-incompetent Ad confirmed targeted cancer-cell-selective transgene expression in human prostate and breast cancer cells, as well as in malignant glioma cells. 39 Considering these findings, we investigated the use of the PEG-Prom to drive expression of the E1A gene, necessary for Ad replication, to create cancer-cell-specific CRCAs.…”