Abstract
We demonstrated previously that rat tyrosine phosphatase r-PTPeta expression was suppressed in rat and human thyroid neoplastic cells, and that restoration of r-PTPeta expression reverted the malignant phenotype. To investigate the potential of this gene for cancer therapy, we generated an adenovirus carrying the r-PTPeta cDNA (Ad-r-PTPeta). This virus infected human thyroid carcinoma cells and overexpressed the r-PTPeta protein. Overexpression of r-PTPeta significantly inhibited the growth of four thyroid carcinoma cell lines. Cell growth inhibition was associated with down-regulation of extracellular signal-regulated kinase 1/2 activity, with increased levels of the cell-cycle inhibitor p27(kip1) protein and with dephosphorylation of PLCgamma1, a substrate of DEP-1, the human homologue of r-PTPeta. Finally, the growth of xenograft tumors induced in athymic mice by anaplastic thyroid carcinoma ARO cells transduced with the Ad-r-PTPeta virus was drastically reduced. These data suggest that gene therapy based on restoration of PTPeta function has potential in the treatment of human thyroid malignant neoplasias.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenocarcinoma, Follicular / enzymology
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Adenocarcinoma, Follicular / genetics
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Adenocarcinoma, Follicular / pathology
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Adenocarcinoma, Follicular / therapy*
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Adenoviridae / genetics
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Animals
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Cell Cycle Proteins / metabolism
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Cell Division / genetics
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Cyclin-Dependent Kinase Inhibitor p27
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Genetic Therapy / methods*
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Genetic Vectors / genetics
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Humans
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Isoenzymes / biosynthesis
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Isoenzymes / genetics
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Isoenzymes / metabolism
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Phospholipase C gamma
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Phosphorylation
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Protein Tyrosine Phosphatases / biosynthesis
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Protein Tyrosine Phosphatases / genetics*
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Protein Tyrosine Phosphatases / metabolism
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Rats
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Thyroid Neoplasms / enzymology
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Thyroid Neoplasms / genetics
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Thyroid Neoplasms / pathology
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Thyroid Neoplasms / therapy*
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Transduction, Genetic
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Tumor Cells, Cultured
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Tumor Suppressor Proteins / metabolism
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Type C Phospholipases / metabolism
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Xenograft Model Antitumor Assays
Substances
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Cdkn1b protein, mouse
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Cdkn1b protein, rat
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Cell Cycle Proteins
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Isoenzymes
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Tumor Suppressor Proteins
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Cyclin-Dependent Kinase Inhibitor p27
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases
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Protein Tyrosine Phosphatases
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Type C Phospholipases
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Phospholipase C gamma