ABSTRACT
Promoter methylation of tumor suppressor gene SOX11 has been reported to contribute to the diagnosis and prognosis of various cancerous diseases, including gastric cancer, hematopoietic malignancies and nasopharyngeal carcinoma. However, there is no data on the diagnostic potential of serum SOX11 promoter methylation in hepatocellular carcinoma (HCC). This study was therefore aimed to investigate the potential role of serum SOX11 promoter methylation as a noninvasive biomarker in the diagnosis of patients with hepatitis B virus (HBV) associated HCC. A total of 205 subjects were retrospectively included, which consisted of 111 HCC patients, 66 chronic hepatitis B (CHB) and 28 healthy controls (HCs). Methylation of SOX11 promoter was determined by methylation-specific polymerase chain reaction. The methylation frequency of serum SOX11 promoter in HCC patients (69.4%, 77/111) was significantly higher than that in CHB patients (13.6%, 9/66; χ2 = 51.467, P<0.001) and HCs (10.7%, 3/28; χ2 = 31.489, P<0.001). There was significant difference of serum SOX11 promoter methylation in HCC patients with vascular invasion (49/58) and those without vascular invasion (28/53; χ2 = 13.058, P<0.001). Furthermore, the sensitivity of 69% was identified for SOX11 methylation in discriminating HCC from CHB, which was significant higher than the sensitivity of 57% for serum alpha-fetoprotein (AFP) (P<0.05). Notably, SOX11 promoter methylation plus AFP showed a sensitivity of 85% in discriminating HCC from CHB. These results suggested that serum SOX11 promoter methylation might serve as a useful and noninvasive biomarker for the diagnosis of HCC.
Subject(s)
Carcinoma, Hepatocellular/virology , DNA Methylation , Hepatitis B, Chronic/blood , Liver Neoplasms/virology , SOXC Transcription Factors/blood , Adult , Carcinoma, Hepatocellular/blood , Carcinoma, Hepatocellular/genetics , Case-Control Studies , Diagnosis, Differential , Female , Hepatitis B virus/isolation & purification , Hepatitis B, Chronic/genetics , Humans , Liver Neoplasms/blood , Liver Neoplasms/genetics , Male , Middle Aged , Promoter Regions, Genetic , Retrospective Studies , SOXC Transcription Factors/genetics , alpha-Fetoproteins/metabolismABSTRACT
Exportin 4 (XPO4) is a novel identified candidate tumour-suppressor gene involved in the pathogenesis of hepatocellular carcinoma (HCC). This study was aimed to determine the clinical features of XPO4 mRNA expression and promoter methylation status in peripheral blood mononuclear cells (PBMCs) of patients with chronic hepatitis B virus (HBV) infection. PBMCs were isolated from 44 HCC, 38 liver cirrhosis (LC), 34 chronic hepatitis B (CHB) patients and 17 healthy controls (HCs). The mRNA level and promoter methylation status of XPO4 were determined by quantitative real-time RT-PCR and methylation-specific PCR, respectively. XPO4 mRNA level of HCC patients was significantly lower compared with LC and CHB patients as well as HCs (all P < 0.01, respectively), and significant differences of the XPO4 mRNA level were found in LC and CHB group than in HCs (LC vs HCs, P < 0.01; CHB vs HCs, P < 0.05). Methylation rate of XPO4 promoter was significantly increased in patients with HCC than in patients with CHB and HCs (both P < 0.05). DNA methylation pattern was responsible for the suppression of XPO4 transcription in the progression of HBV infection (P = 0.000). Furthermore, AFP level was significantly higher in HCC patients with XPO4 methylation than in those without methylation ((8702 ± 15635) µm vs (1052 ± 5370) µm, P < 0.05). In conclusion, transcription of XPO4 gene was gradually decreased and methylation rate of XPO4 promoter was increased with the progression of HBV infection. Methylation status of XPO4 in PBMCs tended to be a noninvasive biomarker to predict HCC and the progression of HBV infection.