Hypermethylation-repressed methionine adenosyltransferase 1A as a potential biomarker for hepatocellular carcinoma

Methionine adenosyltransferase 1A (MAT1A) is inactivated in HCC and may be stimulated by an epigenetic change involving promoter hypermethylation in hepatocarcinogenesis. However, the possible clinical impact and prognosis of this inactivation have not been investigated.

We studied the methylation status of the CpG sites in the promoter region and the mRNA and protein expression of MAT1A in HCC and corresponding adjacent non-tumor tissues using methylation-specific polymerase chain reaction, reverse transcription polymerase chain reaction and immunohistochemistry techniques.

MAT1A promoter methylation was significantly higher in HCC than that in adjacent non-tumor tissues (P < 0.0001). Bisulfite sequencing showed that the four CpG sites were hypermethylated in HCC while hypomethylation was found in the corresponding adjacent non-tumor tissues. Furthermore, MAT1A methylation was significantly associated with protein expression (P = 0.022). Low expression of MAT1A was correlated with larger tumor size, higher tumor-node-metastasis stage, positive hepatitis B surface antigen status and high α-fetoprotein (AFP) serum levels (P < 0.05). MAT1A promoter methylation was also correlated with high AFP serum level (P < 0.05). In univariate survival analysis, low expression of MAT1A was significantly associated with shortened patient survival (P < 0.001). Furthermore, in multivariate analysis, MAT1A expression was found as an independent prognostic factor (P = 0.016).

Our observations suggest that hypermethylation of the MAT1A promoter may be one of the events in the development of HCC. Low expression of MAT1A is likely involved in the progression of the tumor and was found to be an independent factor for poor prognosis of patients with HCC.