Abstract
The development and progression of hepatocellular carcinoma (HCC) is accompanied with persistent oxidative stress, but the molecular basis is not well defined. Superoxide dismutase 2 (SOD2) is an important mitochondrial antioxidant and a key aging factor. Here we investigated the expression and clinical significance of SOD2 in a large cohort of HBV-positive HCC tumors. Both SOD2 mRNA and protein are reduced in human primary HCCs compared with matching liver tissues. Consistently, the SOD2 DNA copy numbers are decreased in HCCs, providing a genetic basis for the decrease in SOD2 mRNA expression. Reduced SOD2 expression in HCCs is correlated with older age, larger tumor size, multiple tumor nodules and tumor emboli, and cancer recurrence. Moreover, low SOD2 expression is strongly associated with poor overall survival (OS) and recurrence-free survival (RFS). Univariate and multivariate Cox regression analyses indicates that SOD2 is an independent prognostic predictor for OS and RFS. Intriguingly, reduced SOD2 mRNA is strongly associated with poor survival in a separate cohort of HCC patients carrying mutant p53. Altogether, our results provide clinical evidence for the importance of SOD2 in tumor progression and mortality, and the close relationship of SOD2 and p53 in HCC.
Highlights
Reactive oxygen species (ROS) are oxygen-containing free radicals and reactive molecules such as superoxide (O2-), hydroxyl (OH-) and hydrogen peroxide (H2O2) [1]
Superoxide dismutase 2 (SOD2) mRNA level was analyzed in 40 pairs of human primary hepatocellular carcinoma (HCC) and matching adjacent non-cancerous liver (NCL) tissues by RT-qPCR
Because TP53 is frequently mutated in liver cancer, we investigated the relationship between TP53 mutations and SOD2 expression in the survival of HCC patients using genomic and clinical data from cBioPortal for Cancer Genomics
Summary
Reactive oxygen species (ROS) are oxygen-containing free radicals and reactive molecules such as superoxide (O2-), hydroxyl (OH-) and hydrogen peroxide (H2O2) [1]. ROS is generated during mitochondrial respiration and in enzyme-catalyzed reactions [2]. Mitochondrial respiration is a main source of ROS due to production of superoxide anion from Complex I and III of the electron transport chain, estimated at 1-2% oxygen consumed by the cell [3]. Superoxide anion is further converted into other ROS species such as hydroxyl free radical and hydrogen peroxide. ROS plays an important regulatory role in many cellular activities such as metabolism and signal transduction [4, 5]. H2O2 regulates protein tyrosine and lipid phosphatases, thereby dictating the signal transduction strength by receptor tyrosine kinases [6, 7]. Under pathological conditions, ROS can reach excessively high levels, which is a major cause of aging and aging-related diseases such as Alzheimer’s disease and cancer [8,9,10]
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