Different ligands can lead to the activation of epidermal growth factor receptor, and the subsequent signal transduction leads to an increase in cellular motility, proliferation, invasion, and blocking of apoptosis, and all of this contributes to the development and progression of cancer. Our studies clarified; 1) The EGFR expression level is reduced during tumor progression or during ligand-induced EGFR activation. 2) ANXA8 and its regulatory pathway may well be alternative, strategic targets for inhibiting tumor metastasis. 3) The molecular pathway of EphA2 signaling and provide insight into the mechanisms that control cancer progression and metastatic spread in cholangiocarcinoma (CC). Therefore, therapeutic strategies that target EphA2 and its downstream effectors may be useful to control CC.