Effect of EZH2/PRC2 modulation in agressive thyroid carcinoma

Abstract

Anaplastic thyroid carcinoma (ATC) is the most aggressive and fatal endocrine cancer. Due to the loss of thyroid cell differentiation, ATC does not uptake iodine, and thus, is refractory to radioiodine therapy. The molecular pathways altered in ATC pathogenesis are associated to mutations in MAPK, inactivation of TP53 and mutations in TERT promoter. However, additional alterations may contribute to ATC aggressiveness and dedifferentiation. In this context, the polycomb complex EZH2/PRC2, which acts in gene silencing by histone modification, emerge as a potential pathway that is overexpressed in different malignancies, including ATC. Moreover, regulatory RNAs, such as microRNAs and long non-coding RNAs, regulate EZH2 function and are also deregulated in ATC. Thus, this project aims to understand the role of PRC2/EZH2 complex in aggressive thyroid cancer by using gene editing methodology via CRISPR/Cas9 to disrupt the human EZH2 gene. For that, in vitro assays (proliferation, viability, apoptosis, invasion and cell migration) and xenotransplant in mice will be performed after the construction of CRISPR/Cas9 + sgRNA EZH2 plasmid to generate EZH2 loss of function in anaplastic thyroid cancer cell lines. Therefore, we expect this study may contribute to a better understanding of aggressive thyroid cancer biology. (AU)