miR-199a-3p displays tumor suppressor functions in papillary thyroid carcinoma

Abstract

Thyroid cancer incidence is rapidly increasing. Papillary Thyroid Carcinoma (PTC), the most frequent hystotype, usually displays good prognosis, but no effective therapeutic options are available for the fraction of progressive PTC patients. BRAF and RET/PTC are the most frequent driving genetic lesions identified in PTC. We developed two complementary in vitro models based on RET/PTC1 oncogene, starting from the hypothesis that miRNAs modulated by a driving PTC-oncogene are likely to have a role in thyroid neoplastic processes. Through this strategy, we identified a panel of deregulated miRNAs. Among these we focused on miR-199a-3p and showed its under-expression in PTC specimens and cell lines. We demonstrated that miR-199a-3p restoration in PTC cells reduces MET and mTOR protein levels, impairs migration and proliferation and, more interesting, induces lethality through an unusual form of cell death similar to methuosis, caused by macropinocytosis dysregulation. Silencing MET or mTOR, both involved in survival pathways, does not recapitulate miR-199a-3p-induced cell lethality, thus suggesting that the cooperative regulation of multiple gene targets is necessary. Integrated analysis of miR-199a-3p targets unveils interesting networks including HGF and macropinocytosis pathways. Overall our results indicate miR-199a-3p as a tumor suppressor miRNA in PTC.

MECHANISMS IN ENDOCRINOLOGY: MicroRNA in diagnostics and therapy of thyroid cancer

“…Overexpression of miR-101 (64) and miR-145 (49), both downregulated in PTC, led to decreased cell proliferation, migration, and invasion. Similar effects were observed for miR-199a-3p, which induced non-apoptotic cell death in a PTC-derived cell line (65). Similarly, miR-291-5p was downregulated in PTC tumors, and the forced expression of the miR suppressed PTC cell proliferation and migration, as well as promoted apoptosis.…”

MicroRNA-613 inhibits cell growth, migration and invasion of papillary thyroid carcinoma by regulating SphK2

“…Aberrant expression of miRNAs can act as tumor suppressors or oncogenes, depending on the cellular function of their targets [7, 8]. Several studies suggest that alterations in miRNA expression contribute to PTC development and progression [9–13]. In our previous study, miRNA-613 was significantly downregulated in PTC tissues compared with adjacent non tumor tissues by miRNA arrays and qRT-PCR analysis [14].…”

MicroRNAs Associated with Shoulder Tendon Matrisome Disorganization in Glenohumeral Arthritis

“…miR-199a species attained prior attention of cancer researchers owing to their contrast features as it can suppress or progress cancer depending on the tissue type [32]. The cells treated with miR-199a-5p were channeled to apoptotic pathways and also underwent an unusual form of cell death called methuosis, which is characterized by vacuole formation and macropinocytosis [33]. The miR-199 family of microRNAs have also been identified to regulate HIF-1α and p53 to facilitate apoptosis [34].…”