Systematic Expression Analysis of Mitochondrial Complex I IdentifiesNDUFS1as a Biomarker in Clear-Cell Renal-Cell Carcinoma

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Abstract

Introduction

Mitochondrial dysfunction is common in cancer, and the mitochondrial electron transport chain is often affected in carcinogenesis. So far, little is known about the expression of the mitochondrial complex I (NADH:ubiquinone oxidoreductase) subunits in clear-cell renal-cell carcinoma (ccRCC).

Materials and Methods

An expression profile of the mitochondrial complex I subunits was determined using the NextBio database. Subsequently, the expression of selected subunits was experimentally validated on mRNA (quantitative real-time polymerase chain reaction) and protein (Western blot analysis, immunohistochemistry) level.

Results

We observed that 7 subunits of the complex I were down-regulated in at least 3 microarray studies. Deregulated mRNA expression was confirmed for NDUFA3, NDUFA, NDUFB1, NDUFB9, NDUFS1, NDUFS8, and NDUFV1. Low NDUFS1 mRNA expression was a significant and independent adverse predictor of a shorter overall survival in our mRNA cohort and the ccRCC cohort of The Cancer Genome Atlas project. NDUFS1 expression was furthermore analyzed on the protein level, and a distinct down-regulation was observed in ccRCC as well as in the chromophobe and the sarcomatoid subtype compared to normal renal tissue.

Conclusion

Expression alterations occur in only a few subunits of the mitochondrial complex I subunits in ccRCC, and altered mRNA and protein expression levels of NDUFS1 may be useful to distinguish between renal-cell carcinoma and normal renal tissue.

Micro-Abstract

Mitochondrial dysfunction is common in cancer. A meta-analysis of published microarray gene expression studies led to the identification of 7 (of 44) down-regulated subunits of the mitochondrial complex I in clear-cell renal-cell carcinoma. NDUFS1 mRNA and protein expression levels were validated and may serve as diagnostic biomarkers. Altered activity of the electron transport chain is related to altered expression of specific subunits.

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