Reduced SOD2 expression is associated with mortality of hepatocellular carcinoma patients in a mutant p53-dependent manner

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.

Role of TGF‐β1/miR‐382‐5p/SOD2 axis in the induction of oxidative stress in CD34+ cells from primary myelofibrosis

“…Among SOD family members, manganese superoxide dismutase 2 (MnSOD‐ SOD2 ) plays an essential role not only in cancer but also in a wide range of stress‐induced diseases due to its localization in the mitochondria, where the production of ROS is higher compared to the other cellular compartments (Inoue et al ., ). In particular, SOD2 has been described as a tumor suppressor gene (Van Remmen et al ., ) and its decreased expression level has been reported in a wide variety of diseases (Wang et al ., ) (Hitchler et al ., ), including hematological malignancies (Hurt et al ., ).…”

“…Two-tailed Student's t-test: **P < .01 versus untreated cells; *P < .05 versus untreated cells. SOD2 has been described as a tumor suppressor gene (Van Remmen et al, 2003) and its decreased expression level has been reported in a wide variety of diseases (Wang et al, 2016) (Hitchler et al, 2008, including hematological malignancies (Hurt et al, 2007).…”

Mitochondrial ROS control of cancer

“…SOD2 contributes to the regulation of cell proliferation, transformation, migration, invasion and angiogenesis primarily through the redox-dependent modulation of the transcription factors NF-KB, HIF-1, AP-1 and p53 100,102–104 . SOD2 deficiency has been shown to have both pro- and antitumorigenic activity 102,105–107 . High SOD2 expression can inhibit cell proliferation directly 108 or sensitize cells to the cytotoxicity of the anti-cancer drugs 109 .…”

Human hepatocellular carcinoma: Protection by melatonin

“…There is a reduction in the mRNA and protein expressions for Mn‐SOD (SOD2) in HCC patients, and that there is a close relationship between low SOD2 levels with p53 mutations in these patients (Wang, Yin et al, ) (Figure ). During hepatocarcinogenesis, upregulation of mitochondrial Ca 2+ uniporter (MCU) increases Ca 2+ uptake toward mitochondria by down‐regulating the ratio for nicotinamide adenine dinucleotide + (NAD + ) to its reduced form (nicotinamide adenine dinucleotid (NADH).…”