Biological models and genes of tumor reversion: cellular reprogramming through tpt1/TCTP and SIAH-1.
Tumor reversion is the process by which some cancer cells lose their malignant phenotype. This study was aimed at defining some of the molecular and phenotypic properties of this process. Biological models of tumor reversion were isolated from human leukemia and breast cancer cell lines by using the H-1 parvovirus as a selective agent. Differential gene expression analysis was performed between the parental malignant cells and their revertants or alternatively between these parental cells and their SIAH-1 transfectant counterparts. These SIAH-1 transfectants have a suppressed malignant phenotype and were used as a control for a viral-free system. Two hundred sixty-three genes were found to be either activated or inhibited during the reversion process, as confirmed by Northern blot analysis or quantitative PCR. Of these, 32% were differentially expressed in all systems, irrespective of whether parvovirus-selected, SIAH-1 overexpressing, or p53 mutant or wild-type cell lines were used, suggesting the existence of a universal mechanism underlying tumor reversion. Translationally Controlled Tumor Protein (tpt1/TCTP) has the strongest differential expression, down-regulated in the reversion of U937- and SIAH-1-overexpressing cells. Inhibition of TCTP expression by anti-sense cDNA or small interfering RNA molecules results in suppression of the malignant phenotype and in cellular reorganization, similar to the effect of SIAH-1. Hence, tumor reversion can be defined at the molecular level, not just as the reversal of malignant transformation, but as a biological process in its own right involving a cellular reprogramming mechanism, overriding genetic changes in cancer, by triggering an alternative pathway leading to suppression of tumorigenicity.
Tuynder
Marcel
M
Molecular Engines Laboratories, 20 Rue Bouvier, 75011 Paris, France.
Susini
Laurent
L
Prieur
Sylvie
S
Besse
Stephanie
S
Fiucci
Giusy
G
Amson
Robert
R
Telerman
Adam
A
D001485:Basement Membrane / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms; D016373:DNA, Antisense / Q000235:genetics*; D004273:DNA, Neoplasm / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020014:K562 Cells; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D034741:RNA, Small Interfering / Q000235:genetics*; D011994:Recombinant Proteins / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D000090324:Tumor Protein, Translationally-Controlled 1; D020298:U937 Cells; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins
D014408:Biomarkers, Tumor; D016373:DNA, Antisense; D004273:DNA, Neoplasm; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; C000715647:TPT1 protein, human; D000090324:Tumor Protein, Translationally-Controlled 1; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins