Transcriptome Analysis of WHV/c-myc Transgenic Mice Implicates Cytochrome P450 Enzyme 17A1 as a Promising Biomarker for Hepatocellular Carcinoma

摘要

Early detection of hepatocellular carcinoma (HCC) is critical for successful treatment and favorable prognosis. To identify novel HCC biomarkers, we used the WHV/c-myc transgenic (Tg) mice, an animal model of hepatocarcinogenesis. By analyzing their gene expression profiling, we investigated differentially expressed genes in livers of wild-type and Tg mice. The cytochrome P450, family 17, subfamily A, polypeptide 1 (CYP17A1), a hepatic P450 enzyme, was revealed to be overexpressed in the liver tissues of Tg mice at both preneoplastic and neoplastic stages. Mouse-to-human validation demonstrated that CYP17A1 mRNA and protein were also significantly increased in human HCC tissues compared with paired nontumor tissues (P = 0.00041 and 0.00011, respectively). Immunohistochemical studies showed that CYP17A1 was overexpressed in 67% (58 of 87) of HCC, and strong staining of CYP17A1 was observed in well-differentiated HCCs. Consistent with this, the median serum levels of CYP17A1 were also significantly higher in patients with HCC (140.2 ng/mL, n = 776) compared with healthy controls (31.4 ng/mL, n = 366) and to those with hepatitis B virus (57.5 ng/mL, n = 160), cirrhosis (46.1 ng/mL, n = 147), lung cancer (27.4 ng/mL, n = 109), and prostate cancer (42.1 ng/mL, n = 130; all P < 0.001). Notably, the elevations were seen in most AFP-negative HCC cases. Altogether, through mouse-to-human search and validation, we found that CYP17A1 is overexpressed in HCCs and it has great potentiality as a noninvasive marker for HCC detection. These results provide a rationale for the future development and clinical application of CYP17A1 measurement to diagnose HCC more precisely. (C) 2016 AACR.