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

ABSTRACT: PURPOSE:We delineated the functions of the hypoxia-inducible factor-1? (HIF1?) 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 HIF1? 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.

SUBMITTER: Minton DR

PROVIDER: S-EPMC4891242 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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

Minton Denise R DR Fu Leiping L Mongan Nigel P NP Shevchuk Maria M MM Nanus David M DM Gudas Lorraine J LJ

Clinical cancer research : an official journal of the American Association for Cancer Research 20160118 11

<h4>Purpose</h4>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.<h4>Experimental design</h4>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 exp ...[more]

PMID: 26783287

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Project description:Clear cell renal carcinoma (ccRC) comprises a set of heterogeneous, fast-progressing pathologies with poor prognosis. Analyzing ccRC progression in terms of modifications at the molecular level may provide us with a broader understanding of the disease, paving the way for improved diagnostics and therapeutics. The role of micro-RNAs (miRs) in cancer by targeting both oncogenes and tumor suppressor genes is widely known. Despite this knowledge, the role of specific miRs and their targets in the progression of ccRC is still unknown. To evaluate the action of miRs and their target genes during ccRC progression, here we implemented a three-step method for constructing miR-gene co-expression networks for each progression stage of ccRC as well as for adjacent-normal renal tissue (NT). In the first step, we inferred all miR-gene co-expression interactions for each progression stage of ccRC and for NT. Afterwards, we filtered the whole miR-gene networks by differential gene and miR expression between successive stages: stage I with non-tumor, stage II with stage I, and so on. Finally, all miR-gene interactions whose relationships were inversely proportional (overexpressed miR and underexpressed genes and vice versa) were kept and removed otherwise. We found that miR-217 is differentially expressed in all contrasts; however, its targets were different depending on the ccRC stage. Furthermore, the target genes of miR-217 have a known role in cancer progression-for instance, in stage II network, GALNTL6 is overexpressed, and it is related to cell signaling, survival, and proliferation. In the stage III network, WNK2, a widely known tumor suppressor, is underexpressed. For the stage IV network, IGF2BP2, a post-transcriptional regulator of MYC and PTEN, is overexpressed. This data-driven network approach has allowed us to discover miRs that have different targets through ccRC progression, thus providing a method for searching possible stage-dependent therapeutic targets in this and other types of cancer.

Dataset Information

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

Publications

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

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