| Summary: | Papillary thyroid carcinoma (PTC) is the most frequent among thyroid tumors and its incidence is continuously increasing. Even though most PTCs are efficiently treated, for the fraction of patients that do not respond to standard therapy and/or progress to metastatic disease effective therapies are still lacking. It has been proposed that a better understanding of the molecular mechanisms underlying PTC development, might be useful to design more effective therapeutic strategies. MicroRNAs (miRNAs), small non-coding RNAs involved in gene expression control, due to their recognized involvement in cancer as well as to their ability to simultaneously regulate multiple biological processes, represent an attractive subject of investigation. The overall aim of this project was to investigate miRNA deregulation in PTC, to better understand the molecular pathways and networks that, in concert with known genetic lesions, operate to drive thyroid malignant transformation. Starting from preliminary results from our laboratory, we exploited previously established in vitro cell models to define miRNA expression profiles associated to a PTC-driving oncogene (RETIPTC1). Among the identified miRNAs, we focused on miR-199a-3p and miR-451a, and investigated their expression and functional role in PTC specimens and cell lines. Here, we show that these miRNAs are underexpressed in PTC and display tumor suppressor functions by inhibiting proliferation and migration of PTC-derived cell lines and by targeting multiple effectors of the AKT/mTOR pathway, a central hub in the molecular networks involved in thyroid carcinogenesis. In addition, we report, for the first time, that miR- 199a-3p induces in PTC cells an unconventional form of non-apoptotic cell death, termed methuosis, associated to macropinocytosis hyperstimulation. Even though the molecular players involved in this form of cell death remain uncharacterized, our data suggest that AKT might play a critical role in this process.
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