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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.

SUBMITTER: Wang R

PROVIDER: S-EPMC4931826 | biostudies-other | 2016 Jun

REPOSITORIES: biostudies-other

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

Wang Ren R Yin Chen C Li Xiao-Xing XX Yang Xian-Zi XZ Yang Yang Y Zhang Mei-Yin MY Wang Hui-Yun HY Zheng X F Steven XF

Aging 20160601 6

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 co ...[more]

PMID: 27221200

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Project description:The DNA-alkylating cytotoxic agent cyclophosphamide (CTX) is commonly used in the clinic to treat hematological malignancies like lymphomas and leukemias as well as solid tumors, but shows dose-dependent potentially life-threatening toxicities and can induce secondary malignancies. Thus, the clinical utility of CTX would be improved if a companion drug could be identified that allows lowering the CTX dose, while maintaining or even increasing its antineoplastic therapeutic efficacy. In mouse models, high-dose CTX (300 mg/kg) is effective in treating T-lymphomas, while low dose (defined here as 100 mg/kg) is ineffective. We previously showed that the HSP90 inhibitor ganetespib potently suppresses T-lymphoma initiation and progression and extends overall survival (OS) in hotspot knockin mice expressing the p53 gain-of-function mutants R175H and R248Q (mutp53) by 30-59%. Here we asked whether ganetespib could potentiate the effect of low-dose CTX (100 mg/kg) in the autochthonous T-lymphoma-bearing mutp53 R248Q mouse model. Indeed, combinatorial CTX/ganetespib synergistically suppresses growth of autochthonous T-lymphomas in R248Q (p53Q/-) but not p53-/- control mice by reducing mutp53 levels and triggering apoptosis. Combinatorial treatment extends progression-free (PFS) and OS in p53Q/- mice significantly longer than in p53-/- mice. Specifically, PFS of p53Q/- mice improves 8.9-fold over CTX alone versus 3.6-fold in p53-/- mice. Likewise, OS of R248Q/- mice improves 3.6-fold, but worsens in p53-/- mice (0.85-fold) over CTX alone. Moreover, half of the p53Q/- mice on combinatorial treatment lived over 60 days, and one animal reached 121 days. In contrast, p53Q/- mice on single-drug treatment and p53-/- mice on any treatment lived less than 24 days. In sum, ganetespib synergizes with a sub-effective dose of CTX in mutp53 T-lymphomas by suppressing tumor growth and extending survival. Our results provide a potential strategy to reduce the effective clinical dose of CTX in mutant p53-bearing malignancies and attenuate CTX toxicity.

Dataset Information

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

Publications

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

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