LEP and obesity due to melanocortin 4 receptor deficiency: In human CRC-derived cell lines, insulin and/or leptin resistance, which usually occurs in obesity, interferes with the activation of mitogen-activated protein kinase 1/2 (MEK1/2) induced by insulin/leptin, which leads to an increase in miR-4443, in turn inhibiting nuclear receptor coactivator (NCOA)-1 and tumor necrosis factor receptor-associated factor (TRAF)-4, possibly causing tumor suppression and decreasing cell invasion [125].