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 enzymes that play a central role in the oxidative metabolism of both xenobiotic and endogenous compounds. Several CYPs are involved in metabolism of oxysterols, which are cholesterol oxidation products whose expression may be dysregulated in inflammation-related diseases including cancer. This study focused on CYP39A1, which can metabolize 24-hydroxycholesterol (24-OH) that plays important roles in the inflammatory response and oxidative 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 induce oxidative stress in CCA cell lines. Immunohistochemistry showed that 70% and 30% of CCA patients had low and high expression of CYP39A1, respectively. Low expression of CYP39A1 demonstrated a significant correlation with metastasis. Our results also revealed that the expression of RUNX2 had a positive correlation with CYP39A1. Low expression of both CYP39A1 (70%) and RUNX2 (37%) was significantly related with poor prognosis 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 study revealed putative roles of the CYP39A1 enzyme in prognostic determination of CCAs.

Expression of oxysterol pathway genes in oestrogen‐positive breast carcinomas

“…Contrary to the results of the present study, an association of CYP7B1 downregulation with poor overall survival of patients with ER+ breast carcinoma was previously reported . Similarly, CYP39A1 hypermethylation predicted poor prognosis in patients with ovarian carcinoma, and low CYP39A1 expression was associated with metastasis and poor prognosis of patients with cholangiocarcinoma . Both enzymes are 7‐hydroxylases, which catabolize and thus reduce the levels of 24‐hydroxycholesterol (CYP39A1), 25‐hydroxycholesterol and 27‐hydroxycholesterol (CYP7B1) in cells .…”

“…37 Similarly, CYP39A1 hypermethylation predicted poor prognosis in patients with ovarian carcinoma, 38 and low CYP39A1 expression was associated with metastasis and poor prognosis of patients with cholangiocarcinoma. 39 Both enzymes are 7-hydroxylases, which catabolize and thus reduce the levels of 24-hydroxycholesterol (CYP39A1), 25-hydroxycholesterol and 27-hydroxycholesterol (CYP7B1) in cells. 24 Interestingly, deletion of CYP7B1 in xenograft models was associated with increased tumour growth and higher circulating levels of 27-hydroxycholesterol, an agonist of ER in breast carcinoma cells.…”

Microarray Analysis of Differentially-Expressed Genes Encoding CYP450 and Phase II Drug Metabolizing Enzymes in Psoriasis and Melanoma

“…We observed a 3.70-fold downregulation CYP39A1 in melanomas ( Figure 2 and Table 3 ). Little is known about CYP39A1 gene expression in skin, but low CYP39A1 expression correlated with increased inflammation and metastasis in cholangiocarcinoma [ 30 ].…”

Comprehensive analysis of DNA methylation and gene expression profiles in cholangiocarcinoma

“…For example, Zhang et al found that 1,2-dichloropropane, a carcinogenic paint remover, could influence the proliferation and apoptosis of cholangiocytes and this effect is mediated through CYP450 [61]. Moreover, Khenjanta et al found that CYP39A1 was down regulated in 70% of CCA patients and low expression of CYP39A1 demonstrated a significant correlation with metastasis [62]. However, the mechanisms of methylation regulation mechanism for these CYP enzymes are still unknown.…”