Furthermore, chronic bile duct injury by exposure to chronic intermittent toxins such as CCl4 provoked the development of ICC in p53-deficient rats by upregulation of oxidative stress markers cyclooxygenase (COX)-2 and inducible nitric oxide synthase (iNOS) in addition to ERBB2 and c-MET, with downregulation of E-cadherin [24]. This evidence concerns the gene NOS2 and intrahepatic cholangiocarcinoma.