miR-191 downregulation plays a role in thyroid follicular tumors through CDK6 targeting
Colamaio, Marianna (2010) miR-191 downregulation plays a role in thyroid follicular tumors through CDK6 targeting. [Tesi di dottorato] (Inedito)
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miR-191 expression is frequently altered in several neoplasias, being upregulated in some, such as pancreatic, colon, lung and prostate carinomas, and downregulated in others, such as severe medulloblastomas and melanomas. I have investigated the expression of miR-191 in thyroid neoplasias. In my thesis I report that miR-191 is downregulated in follicular adenomas and carcinomas, with a reduction that is almost 2-fold higher in follicular carcinomas with respect to adenomas. Conversely it is upregulated in thyroid carcinomas of the papillary histotype (PTCs), in comparison with the normal thyroid tissue. Consistent with a putative tumour suppressor role of miR-191 in the development of thyroid neoplasias of the follicular histotype, functional studies showed that restoration of miR-191 expression in a follicular thyroid cancer cell line reduces cell growth and migration rate. Furthermore, I found that miR-191 negatively regulates the expression of CDK6 protein, involved in cell cycle control, without changing the CDK6 mRNA level and decreases the activity of a luciferase reporter construct containing the CDK6-3'untranslated region. These results demonstrate that miR-191 regulates CDK6 at the posttranscriptional level, resulting in inhibition of cell proliferation and migration of the follicular thyroid carcinoma cell line; I will show that restoration of miR-191 expression reduces cell proliferation leading to an increased number of the cells in the G1 phase of the cell cycle. Finally, in follicular adenomas and carcinomas, we immunohistochemically detected CDK6 over-expression, suggesting that miR-191 may have a pathogenic role in thyroid cancer by controlling CDK6 expression.
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