Abstract
BackgroundMechanisms underlying hepatocellular carcinoma (HCC) development are largely unknown. The role of trace elements and proteins regulating metal ions homeostasis, i.e. metallothioneins (MTs), recently gained an increased interest. Object of the study was to investigate the role of promoter DNA methylation in MTs transcriptional regulation and the possible prognostic significance of serum trace elements in HCC.MethodsForty-nine HCC patients were enrolled and clinically characterized. Cu, Se, and Zn contents were measured by Inductively Coupled Plasma Mass Spectrometry in the serum and, for a subset of 27 patients, in HCC and homologous non-neoplastic liver (N) tissues. MT1G and MT1H gene expression in hepatic tissues was assessed by Real-Time RT-PCR and the specific promoter DNA methylation by Bisulfite-Amplicon Sequencing.ResultsPatients with Cu serum concentration above the 80th percentile had a significantly decreased survival rate (P < 0.001) with a marked increased hazard ratio for mortality (HR 6.88 with 95% CI 2.60–18.23, P < 0.001). Se and Zn levels were significantly lower in HCC as compared to N tissues (P < 0.0001). MT1G and MT1H gene expression was significantly down-regulated in HCC as compared to N tissues (P < 0.05). MTs promoter was hypermethylated in 9 out of the 19 HCC tissues showing MTs down-regulation and methylation levels of three specific CpGs paralleled to an increased mortality rate among the 23 patients analyzed (P = 0.015).Conclusions MT1G and MT1H act as potential tumor suppressor genes regulated through promoter DNA methylation and, together with serum Cu concentrations, be related to survival rate in HCC.
Highlights
Liver cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide, and hepatocellular carcinoma (HCC) is the most frequent primary liver cancer [1]
They had a mean age of 70.8 ± 6.9 years and were all free from hepatitis B or C infections, according to the enrolment criteria
Analyses were performed for possible correlation among serum concentrations of Cu, Zn, and Se (Supplementary Table 2) and for correlation among the serum trace elements and clinical variables (Supplementary Table 3)
Summary
Liver cancer is the sixth most commonly diagnosed cancer and the fourth leading cause of cancer death worldwide, and hepatocellular carcinoma (HCC) is the most frequent primary liver cancer [1]. In addition to iron, whose overload is associated to the production of free oxygen radicals and subsequent damage of nucleic acid as the possible trigger for hepatocarcinogenesis [3], Cu, Se, and Zn have been evoked in association with primary liver cancers development [4, 5]. MTs are low molecular weight cysteine-rich intracellular proteins capable to bind essential and toxic metals They lead a pivotal role in the cellular functions of detoxification and protection against oxidative stress, due to their ability to scavenge free radicals [10].
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