Abstract
The regulatory transcriptional factor PATZ1 is constantly downregulated in human thyroid cancer where it acts as a tumour suppressor by targeting p53-dependent genes involved in Epithelial-Mesenchymal Transition and cell migration. The aim of the present work was to elucidate the upstream signalling mechanisms regulating PATZ1 expression in thyroid cancer cells. The bioinformatics search for microRNAs able to potentially target PATZ1 led to the identification of several miRNAs. Among them we focused on the miR-29b since it was found upregulated in rat thyroid differentiated cells transformed by the Ha-Ras oncogene towards a high proliferating and high migratory phenotype resembling that of anaplastic carcinomas. Functional assays confirmed PATZ1 as a target of miR-29b, and, consistently, an inverse correlation between miR-29b and PATZ1 protein levels was found upon induction of Ha-Ras oncogene expression in these cells. Interestingly, restoration of PATZ1 expression in rat thyroid cells stably expressing the Ha-Ras oncogene decreased cell proliferation and migration, indicating a key role of PATZ1 in Ras-driven thyroid transformation. Together, these results suggest a novel mechanism regulating PATZ1 expression based on the upregulation of miR-29b expression induced by Ras oncogene.
Highlights
Epithelial-mesenchymal transition and in vivo tumorigenic potential[5]
In order to identify potentially conserved miRNA being able to down-modulate the expression of PATZ1 protein, we used the www.microRNA.org web platform that is based on the miRanda application[31] and uses the mirSVR predicted target site scoring method, giving a down-regulation score and identifying a significant number of experimentally determined non-canonical and non-conserved sites[32]
As indicated by the PhastCons score higher than cutoff, the targeting sites of these PATZ1-targeting miRNAs on the 3′ -UTR of PATZ1 are extremely conserved among different species
Summary
The aim of our studies has been to unveil the mechanisms that could regulate PATZ1 expression in thyroid cancer. Among them the top scored upregulated miRNA was miR-21, which has been shown to play an important role in oncogenic Ras-induced cell proliferation in vitro and to be regulated in human PTCs29,30. Other miRNAs, including miR-29b, appear significantly upregulated downstream of oncogenic Ras[28]. This miRNA is predicted by bioinformatic analysis to be able to target PATZ1. We confirmed the tumour suppressor activity of PATZ1 in thyroid cancer since the restoration of its expression in the Ras-transformed thyroid cells significantly decreased cell proliferation and migration
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