Mitogen-Inducible Gene-6 Mediates Feedback Inhibition from Mutated BRAF towards the Epidermal Growth Factor Receptor and Thereby Limits Malignant Transformation

摘要: BRAF functions in the RAS-extracellular signal-regulated kinase (ERK) signaling cascade. Activation of this pathway is necessary to mediate transforming potential oncogenic BRAF, however, it may also cause a negative feedback that inhibits epidermal growth factor receptor (EGFR). Mitogen-inducible gene-6 (MIG-6) potent inhibitor EGFR and has been demonstrated function as tumor suppressor. As MIG-6 can be induced via RAS-ERK signaling, we investigated its involvement regulatory loop. Focus formation assays were performed significantly reduces malignant transformation by BRAF. Although genetic interaction was mirrored physical between did not observe direct regulation activity MIG-6. Interestingly, selective chemical suppressed similar degree MIG-6, whereas combining these approaches had no synergistic effect. By analyzing range mutated wildtype cell line models, could show V600E causes strong upregulation which mediated at transcriptional level resulted downregulation activation. This loop operational tumors, shown analysis almost 400 patients with papillary thyroid cancer (PTC). Presence correlated increased expression on one hand, inactivation PI3K/AKT other hand. Importantly, observed more aggressive disease phenotype when coexisted low expression. Finally, methylation data revealed higher decreased Taken together, demonstrate efficiently cellular driven orchestrating circuit directed towards EGFR.