Progression elevated gene-3, PEG-3, induces genomic instability in rodent and human tumor cells.
Genomic instability is a fundamental component of cancer progression. Subtraction hybridization identified a novel rodent gene, progression elevated gene-3 (PEG-3) whose expression directly correlates with cancer aggressiveness and progression. Moreover, ectopic expression of PEG-3 in rodent or human tumor cells produces an aggressive transformed phenotype. We demonstrate that PEG-3 expression in rodent tumor cells correlates directly with genomic instability as characterized by alterations in chromosome composition and structure. Additionally, elevated endogenous or ectopic expression of PEG-3 in rodent and human tumor cells, respectively, enhances gene amplification, as monitored by resistance to methothrexate (MTX) and amplification of the dihydrofolate reductase (dhfr) gene. Stable expression of PEG-3 in normal cloned rat embryo fibroblast (CREF) cells marginally elevates MTX resistance, but morphology remains unaltered and anchorage independence is not induced, suggesting that these phenotypes are separable in immortal cells and gene amplification may precede the acquisition of morphological and oncogenic transformation. The present studies document that stable, inducible, and transient expression of PEG-3 in cancer cells augments genomic instability. In these contexts, one mechanism by which PEG-3 influences cancer progression may be by preferentially facilitating the development of genomic changes in evolving cancer cells.
Su
Zao-Zhong
ZZ
Department of Urology, Herbert Irving Comprehensive Cancer Center, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Gopalkrishnan
Rahul V
RV
Narayan
Gopeshwar
G
Dent
Paul
P
Fisher
Paul B
PB
D000818:Animals; D000943:Antigens, Differentiation; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002277:Carcinoma / Q000473:pathology / Q000503:physiopathology; D018797:Cell Cycle Proteins; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D002869:Chromosome Aberrations; D019008:Drug Resistance, Neoplasm; D004622:Embryo, Mammalian; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000502:physiology; D005784:Gene Amplification; D016678:Genome; D006801:Humans; D008297:Male; D008727:Methotrexate / Q000494:pharmacology; D051379:Mice; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000473:pathology / Q000503:physiopathology; D054645:Protein Phosphatase 1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D013762:Tetrahydrofolate Dehydrogenase / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000473:pathology / Q000503:physiopathology
D000943:Antigens, Differentiation; D000964:Antimetabolites, Antineoplastic; D018797:Cell Cycle Proteins; D008727:Methotrexate; D009363:Neoplasm Proteins; D054645:Protein Phosphatase 1; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D013762:Tetrahydrofolate Dehydrogenase; C489287:Ppp1r15a protein, rat; C087519:PPP1R15A protein, human; C513256:Ppp1r15a protein, mouse