Association of CYP39A1, RUNX2 and Oxidized Alpha-1 Antitrypsin Expression in Relation to Cholangiocarcinoma Progression

Abstract

Cytochrome P450 (CYP) enzymes are a large family of constitutive and inducible mono-oxygenase enzymesthat play a central role in the oxidative metabolism of both xenobiotic and endogenous compounds. SeveralCYPs are involved in metabolism of oxysterols, which are cholesterol oxidation products whose expression maybe dysregulated in inflammation-related diseases including cancer. This study focused on CYP39A1, whichcan metabolize 24-hydroxycholesterol (24-OH) that plays important roles in the inflammatory response andoxidative stress. We aimed to investigate the expression status of CYP39A1 and its transcription factor (RUNX2)in relation to clinical significance in cholangiocarcinoma (CCAs) and to determine whether 24-OH could induceoxidative stress in CCA cell lines. Immunohistochemistry showed that 70% and 30% of CCA patients hadlow and high expression of CYP39A1, respectively. Low expression of CYP39A1 demonstrated a significantcorrelation with metastasis. Our results also revealed that the expression of RUNX2 had a positive correlationwith CYP39A1. Low expression of both CYP39A1 (70%) and RUNX2 (37%) was significantly related with poorprognosis of CCA patients. Interestingly, oxidized alpha-1 antitrypsin (ox-A1AT), an oxidative stress marker,was significantly increased in CCA tissues in which CYP39A1 and RUNX2 were down regulated. Additionally,immunocytochemistry showed that 24-OH could induce ox-A1AT in CCA cell lines. In conclusion, our studyrevealed putative roles of the CYP39A1 enzyme in prognostic determination of CCAs.