Figure 3.

Estrogen non-genomic signaling pathway and estrogen-induced ROS generation in thyrocyte. The non-genomic signaling of E2 occurs via the membrane-bound receptor mER, which stimulates activation of the MAP kinase and the PI3 kinase signaling pathways (left). Due to the chromosomal rearrangement of the tyrosine kinase receptor TRKA, PET/PTC genes, BRAF gene, and RAS gene mutation, aberrant activation of the tyrosine kinase pathway occurs. Additionally, the PI3K AKT pathway may also be abnormally activated by mutational inactivation of PTEN. E2 stimulates these pathways [61]. In addition, E2 stimulates NOX4 to product ROS, as well as generates ROS through its own metabolization [65]. NOX4 located in the plasma membrane, endoplasmic reticulum, and nuclear membrane. ROS is able to reach nuclear, then promote some alterations which help thyroid carcinogenesis. DUOX: dual oxidase; E2: estrogen; NOX4: NAPDH oxidase 4; ROS: reactive oxygen species; TPO: thyroperoxidase.