Title | Role of NADH Dehydrogenase (Ubiquinone) 1 Alpha Subcomplex 4-Like 2 in Clear Cell Renal Cell Carcinoma. |
Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Minton DR, Fu L, Mongan NP, Shevchuk MM, Nanus DM, Gudas LJ |
Journal | Clin Cancer Res |
Volume | 22 |
Issue | 11 |
Pagination | 2791-801 |
Date Published | 2016 06 01 |
ISSN | 1078-0432 |
Keywords | Animals, Autophagy, Carcinoma, Renal Cell, Cell Line, Tumor, Cell Proliferation, Electron Transport Complex I, Gene Expression, Gene Knockdown Techniques, Kidney Neoplasms, Male, Metabolic Networks and Pathways, Mice, Inbred C57BL, Mice, Transgenic, Mitochondria |
Abstract | PURPOSE: 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. EXPERIMENTAL DESIGN: 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. 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. 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. CONCLUSIONS: Collectively, our data show that NDUFA4L2 is a novel molecular target for ccRCC treatment. Clin Cancer Res; 22(11); 2791-801. ©2016 AACR. |
DOI | 10.1158/1078-0432.CCR-15-1511 |
Alternate Journal | Clin. Cancer Res. |
PubMed ID | 26783287 |
PubMed Central ID | PMC4891242 |
Grant List | T32 CA062948 / CA / NCI NIH HHS / United States |