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.

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.

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

• Journal Article Type: Article
• Acceptance Date: Jan 7, 2016
• Online Publication Date: Jan 18, 2016
• Publication Date: Jun 1, 2016
• Deposit Date: Jan 28, 2016
• Publicly Available Date: Jan 28, 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
• DOI: https://doi.org/10.1158/1078-0432.ccr-15-1511
• Public URL: https://nottingham-repository.worktribe.com/output/772453
• Publisher URL: http://clincancerres.aacrjournals.org/content/early/2016/01/16/1078-0432.CCR-15-1511