Il miR-214 provoca un cambiamento metabolico e alterazioni molecolari durante la progressione del melanoma ​

Melanoma is the most lethal type of skin cancer due to its metastatic traits leading to poor prognosis. This study aims to investigate the role of the pro-metastatic miR-214 on tumor cell metabolism. We demonstrated that miR-214 overexpression leads to increased glycolysis and reduced mitochondrial functions. In fact, increased glucose uptake, lactate production and PPP flux were evidenced along with reduced TCA and ETC fluxes, ATP production and elevated ROS levels. Increased mitochondrial stress markers and decreased ETC complex activities as well as altered mitochondrial morphology were found. Tumor cells relying on glycolysis accumulate ROS, which can induce metabolic reprogramming. However, upon mtROS scavenging via MitoQ, restoration of mitochondrial damage and ATP production were observed while glycolysis remained upregulated, thus suggesting that, in this model, glycolysis is independent to altered mtROS. Furthermore, decreased expression of proteins involved in mitochondrial dynamics, such as MFN1, MFN2, OPA1, and DRP1, was observed. In addition, when the miR-214 direct target MFN2 was overexpressed in miR-214-overexpressing cells improved mitochondrial health but no alteration in glycolysis was found. miR-214 overexpressing cells also showed hyperactivation of AMPK, which is known to control metabolism. Considering that specific AMPK phosphorylation is controlled by the phosphatase PP2C-α, a putative miR-214 direct target, glycolysis regulation could occur by an independent mechanism, for instance via p-AMPK. Overall, the findings presented here suggest that miR-214 triggers the Warburg effect in melanoma cells by controlling glycolysis and mitochondria in an independent manner. However, further in vitro and in vivo investigations are required to fully understand the molecular mechanisms underlying these effects.