Ferraro, Angelo (2011) Biological function of Cl 2 gene and it’s role in thyroid cancer. [Tesi di dottorato] (Inedito)

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Abstract

Here I report data to support a tumor suppressor role of the Cl 2 gene. Indeed, I detected a drastic reduction, of Cl 2 gene expression in almost all thyroid carcinomas analyzed, with respect to normal thyroid, with the lowest expression levels observed in the follicular variants of papillary carcinomas. Loss of heterozygosity and CpG hypermethylation at the second exon likely accounts for Cl 2 downregulation in thyroid carcinomas. A drastic reduction in Cl 2 expression, with respect to normal counterpart tissues, was also observed in breast, colon and ovarian carcinomas. The restoration of Cl 2 expression in two human thyroid anaplastic carcinoma cell lines leads to the suppression of the malignant phenotype associated with a higher susceptibility to apoptosis. The development of thyroid adenomas and ovarian carcinomas in Cl knock-out mice validates the tumor suppressor role of Cl 2 gene. Finally, transgenic mice for RET/PTC1 oncogene crossed with the Cl 2 knock-out mice developed much more aggressive thyroid carcinomas compared with those observed in the single mutant RET/PTC 1 mice. Therefore, these results taken together indicate Cl 2 as a putative tumor suppressor gene in the process of human thyroid carcinogenesis.

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