Endocrine Abstracts

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. Among thyroid carcinomas, anaplastic thyroid cancer (ATC) is the most aggressive and lethal tumor, which grows very rapidly, invades adjacent tissues and metastasizes, causing death in 1 year from diagnosis. We recently showed that in thyroid cancer PATZ1 expression is downregulated compared to normal thyroid and is further downregulated in follicular (FTC), poorly differentiated (PDTC) and ATC compared to the papillary (PTC) histotype, suggesting PATZ1 downregulation may be involved in late steps of thyroid tumor progression. Consistently, restoration of PATZ1 expression in thyroid cancer cell lines inhibited cellular migration in vitro and partially reverted the epithelial–mesenchymal transition in vivo. In order to investigate the upstream signaling causing PATZ1 downregulation during thyroid transformation we previously employed an inducible cellular system, in which the oncogenic Ras^V12 could be induced by tamoxifen in FRTL-5 rat thyroid cells, causing complete malignant transformation towards an undifferentiated phenotype. In this cell system, as well as in FRTL-5 cells stably expressing the Ras^V12 oncogene, we identified miR-29b as a miRNA specifically upregulated, which targets and downregulates PATZ1 expression downstream of Ras. This is consistent with previous studies showing that in PTC, where PATZ1 is less downregulated, Ras mutations are hardly detected, while in FTC, PDTC and ATC, where PATZ1 is more strongly downregulated, mutations in Ras genes are more frequently found. Here we identify a fundamental role for downregulation of PATZ1 in driving rat thyroid cell transformation by oncogenic Ras. Indeed, PATZ1 overexpression inhibits proliferation and migration of Ras-transformed cells, suggesting that its downregulation is required for Ras-induced thyroid carcinogenesis. Overall, our work demonstrated that PATZ1 is a pivotal regulator acting downstream of miR29b to suppress thyroid cell transformation driven by oncogenic Ras, highlighting a new potential therapeutic target to fight highly malignant thyroid cancer.