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Role of NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex 4-Like 2 in Clear Cell Renal Cell Carcinoma

Minton, Denise R.; Fu, Leiping; Mongan, Nigel P.; Shevchuk, Maria M.; Nanus, David M.; Gudas, Lorraine J.

Authors

Denise R. Minton

Leiping Fu

Maria M. Shevchuk

David M. Nanus

Lorraine J. Gudas



Abstract

PURPOSE

We delineated the functions of the HIF1α target NADH Dehydrogenase (Ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) in ccRCC and characterized NDUFA4L2 as a novel molecular target for ccRCC treatment.

EXPERIMENTAL DESIGN

We evaluated normal kidney and ccRCC patient microarray and RNAseq data from Oncomine and The Cancer Genome Atlas (TCGA) for NDUFA4L2 mRNA levels and the clinical implications of high NDUFA4L2 expression. Additionally, we examined normal kidney and ccRCC patient tissue samples, human ccRCC cell lines, and murine models of ccRCC for NDUFA4L2 mRNA and protein expression. Utilizing shRNA, we performed NDUFA4L2 knockdown experiments and analyzed the proliferation, clonogenicity, metabolite levels, cell structure, and autophagy in ccRCC cell lines in culture.

RESULTS

We found that NDUFA4L2 mRNA and protein are highly expressed in ccRCC samples but undetectable in normal kidney tissue samples, and that NDUFA4L2 mRNA expression correlates with tumor stage and lower overall survival. Additionally, we demonstrated that NDUFA4L2 is a HIF1α target in ccRCC and that NDUFA4L2 knockdown has a profound anti-proliferative effect, alters metabolic pathways, and causes major stress in cultured RCC cells.

CONCLUSIONS

Collectively, our data show that NDUFA4L2 is a novel molecular target for ccRCC treatment.

Journal Article Type Article
Publication Date Jun 1, 2016
Journal Clinical Cancer Research
Print ISSN 1078-0432
Electronic ISSN 1557-3265
Publisher American Association for Cancer Research
Peer Reviewed Peer Reviewed
Volume 22
Issue 11
Pages 2791-2801
APA6 Citation Minton, D. R., Fu, L., Mongan, N. P., Shevchuk, M. M., Nanus, D. M., & Gudas, L. J. (2016). Role of NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex 4-Like 2 in Clear Cell Renal Cell Carcinoma. Clinical Cancer Research, 22(11), 2791-2801. https://doi.org/10.1158/1078-0432.ccr-15-1511
DOI https://doi.org/10.1158/1078-0432.ccr-15-1511
Publisher URL http://clincancerres.aacrjournals.org/content/early/2016/01/16/1078-0432.CCR-15-1511
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf

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Clin Cancer Res-2016-Minton-1078-0432.CCR-15-1511.pdf (4.7 Mb)
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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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