Abstract

Thyroid cancer is one of the most frequent malignancies of the endocrine system, and its incidence is predicted to become the fourth leading cancer diagnosis by 2030. In spite of the progressive knowledge of the molecular mechanisms involved in thyroid transformation, its prognosis remains unpredictable and the identification of new biological markers are needed in addition to already known molecules, to correctly stratify patients at risk of recurrence and progression, eventually providing new targeted therapies. We recently showed that the transcriptional regulator PATZ1 is constantly down-regulated in human thyroid cancer and acts as a tumor suppressor in thyroid cancer cell lines by targeting p53-dependent genes involved in Epithelial-Mesenchymal Transition and cell migration. The aim of the present work was to elucidate the upstream signaling pathway regulating PATZ1 expression during thyroid transformation. We first identified miR-23b and miR-29b to specifically target PATZ1 expression, which was inversely correlated to their expression in rat thyroid cells stimulated to proliferate with Thyroid-stimulating hormone (TSH). Next, using an inducible cell system, we found that miR-29b was up-regulated by oncogenic Ras during transformation of FRTL-5 rat thyroid cells toward an undifferentiated phenotype resembling that of anaplastic carcinomas and characterized by the acquisition of a migratory and invasive behavior. Conversely, PATZ1 was down-regulated, with an inverse correlation compared to miR-29b expression, and was specifically targeted by miR-29b in untransformed FRTL-5 cells. Restoration of PATZ1 expression in FRTL-5 cells stably expressing oncogenic Ras inhibited cell proliferation and migration, indicating a key role of PATZ1 in Ras-driven thyroid transformation. These results confirm the tumor suppressor role of PATZ1 in thyroid cancer and suggest that its downregulation in thyroid cancer requires the activation of Ras GTPase signaling via miR-29b.

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