Thyroid cancer is the most prevalent endocrine malignancy, and papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy. While PTC generally has a favorable prognosis, a subset dedifferentiates into aggressive forms. However, the molecular mechanisms responsible for aggressiveness and dedifferentiation are still poorly understood. We previously showed that HMGA2, a non-histone architectural transcription factor overexpressed in PTC, is involved in cell invasion. This study aimed to further analyze the role of HMGA2 in PTC tumorigenesis by exploring the expression of thyroid-specific and EMT-related genes following HMGA2 knockdown in thyroid cancer cell lines. Then, the clinical relevance of our data was evaluated in vivo. HMGA2 silencing did not modulate the expression of EMT related genes but led to the increased expression of thyroid differentiation genes. Our data also suggest that the MAPK pathway induces thyroid cell dedifferentiation through HMGA2. On the other hand, forskolin, promoting thyroid differentiation, decreased HMGA2 expression. The negative correlations between HMGA2 and thyroid-specific gene expressions were confirmed in a transgenic mouse model of PTC and in human PTC. Finally, we showed that HMGA2 inhibition by suramin reduced cell invasion and induced differentiation expression in vitro, indicating a new therapeutic strategy for treating thyroid cancer.

Thyroid cancer is the most prevalent endocrine malignancy, and papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Although the prognosis is generally favorable, a better understanding of the molecular mechanisms involved in this pathology could lead to new treatment opportunities. Dysregulation of miRNA expression has been correlated with tumor development, and miR-1179 has been previously identified as one of the most downregulated miRNAs in PTC. This study aimed to explore the role of miR-1179 in thyroid tumorigenesis. miR-1179 was overexpressed in the TPC-1, B-CPAP, and HTori-3 thyroid cell lines to characterize its function and identify mRNA targets. The relevance of our data for human PTC was then addressed by analyzing TCGA and independent PTC. We showed that miR-1179 triggered apoptosis and inhibited cell migration. We identified ELF3 as a direct target of miR-1179 and other effectors, including NOTCH3 and CX3CL1. Finally, we revealed the existence of an inverse correlation between decreased expression of miR-1179 and increased expression of ELF3, NOTCH3, and CX3CL1 mRNA in human PTC. Our findings suggest that miR-1179 is a tumor suppressor gene and that its loss may contribute to thyroid tumor progression by promoting the expression of ELF3, NOTCH3, and CX3CL1.