title: Role of NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex 4-Like 2 in Clear Cell Renal Cell Carcinoma.
abstract: We delineated the functions of the hypoxia-inducible factor-1α (HIF1α) target NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) in clear cell renal cell carcinoma (ccRCC) and characterized NDUFA4L2 as a novel molecular target for ccRCC treatment.
  
  
  
  We evaluated normal kidney and ccRCC patient microarray and RNAseq data from Oncomine and The Cancer Genome Atlas for NDUFA4L2 mRNA levels and the clinical implications of high NDUFA4L2 expression. In addition, 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 short hairpin RNA, we performed NDUFA4L2 knockdown experiments and analyzed the proliferation, clonogenicity, metabolite levels, cell structure, and autophagy in ccRCC cell lines in culture.
  
  
  
  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. In addition, we demonstrated that NDUFA4L2 is an HIF1α target in ccRCC and that NDUFA4L2 knockdown has a profound antiproliferative effect, alters metabolic pathways, and causes major stress in cultured RCC cells.
  
  
  
  Collectively, our data show that NDUFA4L2 is a novel molecular target for ccRCC treatment. Clin Cancer Res; 22(11); 2791-801. ©2016 AACR.
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College (WCMC) of Cornell University, New York, New York. Weill Cornell Graduate School of Medical Sciences-Pharmacology Program, WCMC, New York, New York. Department of Pathology, New York University (NYU) School of Medicine, New York, New York.
authors.forename: Denise R
authors.initials: DR
authors.lastname: Minton
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College (WCMC) of Cornell University, New York, New York.
authors.forename: Leiping
authors.initials: L
authors.lastname: Fu
authors.affiliation: Faculty of Medicine and Health Sciences, School of Veterinary Medicine and Science, The University of Nottingham, Sutton Bonington Campus, Loughborough, United Kingdom.
authors.forename: Nigel P
authors.initials: NP
authors.lastname: Mongan
authors.affiliation: Department of Pathology and Laboratory Medicine, WCMC of Cornell University, New York, New York. Meyer Cancer Center, WCMC of Cornell University, New York, New York.
authors.forename: Maria M
authors.initials: MM
authors.lastname: Shevchuk
authors.affiliation: Meyer Cancer Center, WCMC of Cornell University, New York, New York. Division of Hematology and Medical Oncology of the Department of Medicine, WCMC of Cornell University, New York, New York.
authors.forename: David M
authors.initials: DM
authors.lastname: Nanus
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College (WCMC) of Cornell University, New York, New York. Meyer Cancer Center, WCMC of Cornell University, New York, New York. ljgudas@med.cornell.edu.
authors.forename: Lorraine J
authors.initials: LJ
authors.lastname: Gudas
mesh_terms: D000818:Animals; D001343:Autophagy; D002292:Carcinoma, Renal Cell / Q000201:enzymology* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D042967:Electron Transport Complex I / Q000502:physiology*; D015870:Gene Expression; D055785:Gene Knockdown Techniques; D007680:Kidney Neoplasms / Q000201:enzymology* / Q000473:pathology; D008297:Male; D053858:Metabolic Networks and Pathways; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000473:pathology
chemical_list: C000625979:NDUFA4L2 protein, human; D042967:Electron Transport Complex I