STAT3 and cancer: While tyrosine phosphorylation by Janus Kinases (JAK), represents the main activation mechanism of STATs, alternative mechanisms, such as the interaction with HIF signaling pathway, phosphorylation of STAT3 on S727 (134), and regulation of activity and nuclear traffic by small GTPases (135), appear to play important roles that connect STAT3 oncogenic activities with deregulated metabolism in cancer cells.