NDUFA4L2 is associated with clear cell renal cell carcinoma malignancy and is regulated by ELK1

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Abstract

Background

Clear cell renal cell carcinoma (ccRCC) is the most common and lethal cancer of the adult kidney. However, its pathogenesis has not been fully understood till now, which hinders the therapeutic development of ccRCC. NADH dehydrogenase (ubiquinone) 1 alpha subcomplex 4-like 2 (NDUFA4L2) was found to be upregulated and play an important role in ccRCC. We aimed to further investigate the underlying mechanisms by which NDUFA4L2 exerted function and its expression level was upregulated.

Methods

The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data were mined to verify the change of NDUFA4L2 expression level in ccRCC tissues. The correlation between expression level of NDUFA4L2 and cell proliferation/apoptosis was explored by Gene Set Enrichment Analysis (GSEA). Protein-protein interaction (PPI) network of NDUFA4L2 was constructed. Biological process and involved pathways of NDUFA4L2 were analyzed by gene ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway. The transcription factors (TFs) which can induce the expression of NDUFA4L2 were explored in clinical samples by correlation analysis and its regulation on the expression of NDUFA4L2 was verified by knockdown experiment.

Results

NDUFA4L2 was verified to be overexpressed in ccRCC tissues and its expression level was increased accordingly as the American Joint Committee on Cancer (AJCC) stage progressed. A high NDUFA4L2 level predicted the poor prognosis of ccRCC patients and correlated with enhanced cell proliferation and anti-apoptosis. NDUFA4L2 may interact with 14 tumor-related proteins, participate in growth and death processes and be involved in ccRCC-related pathways, such as insulin-like growth factor 1 (IGF-1), mammalian target of Rapamycin (mTOR) and phosphoinositide 3 kinase serine/threonine protein kinase (PI3K/AKT). ETS domain-containing protein ELK1 level positively correlated with the level of NDUFA4L2 in ccRCC tissues and ELK1 could regulate the expression of NDUFA4L2 in ccRCC cells.

Discussion

NDUFA4L2 upregulation was associated with ccRCC malignancy. NDUFA4L2 expression was regulated by ELK1 in ccRCC cells. Our study provided potential mechanisms by which NDUFA4L2 affected ccRCC occurrence and progression.

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Most cited references 20

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The mTOR Signalling Pathway in Human Cancer

Helena Pópulo, José Manuel Lopes, Paula Soares (2012)

The conserved serine/threonine kinase mTOR (the mammalian target of rapamycin), a downstream effector of the PI3K/AKT pathway, forms two distinct multiprotein complexes: mTORC1 and mTORC2. mTORC1 is sensitive to rapamycin, activates S6K1 and 4EBP1, which are involved in mRNA translation. It is activated by diverse stimuli, such as growth factors, nutrients, energy and stress signals, and essential signalling pathways, such as PI3K, MAPK and AMPK, in order to control cell growth, proliferation and survival. mTORC2 is considered resistant to rapamycin and is generally insensitive to nutrients and energy signals. It activates PKC-α and AKT and regulates the actin cytoskeleton. Deregulation of multiple elements of the mTOR pathway (PI3K amplification/mutation, PTEN loss of function, AKT overexpression, and S6K1, 4EBP1 and eIF4E overexpression) has been reported in many types of cancers, particularly in melanoma, where alterations in major components of the mTOR pathway were reported to have significant effects on tumour progression. Therefore, mTOR is an appealing therapeutic target and mTOR inhibitors, including the rapamycin analogues deforolimus, everolimus and temsirolimus, are submitted to clinical trials for treating multiple cancers, alone or in combination with inhibitors of other pathways. Importantly, temsirolimus and everolimus were recently approved by the FDA for the treatment of renal cell carcinoma, PNET and giant cell astrocytoma. Small molecules that inhibit mTOR kinase activity and dual PI3K-mTOR inhibitors are also being developed. In this review, we aim to survey relevant research, the molecular mechanisms of signalling, including upstream activation and downstream effectors, and the role of mTOR in cancer, mainly in melanoma.

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Induction of the mitochondrial NDUFA4L2 protein by HIF-1α decreases oxygen consumption by inhibiting Complex I activity.

Daniel Tello, Eduardo Balsa, Bárbara Acosta-Iborra … (2011)

The fine regulation of mitochondrial function has proved to be an essential metabolic adaptation to fluctuations in oxygen availability. During hypoxia, cells activate an anaerobic switch that favors glycolysis and attenuates the mitochondrial activity. This switch involves the hypoxia-inducible transcription factor-1 (HIF-1). We have identified a HIF-1 target gene, the mitochondrial NDUFA4L2 (NADH dehydrogenase [ubiquinone] 1 alpha subcomplex, 4-like 2). Our results, obtained employing NDUFA4L2-silenced cells and NDUFA4L2 knockout murine embryonic fibroblasts, indicate that hypoxia-induced NDUFA4L2 attenuates mitochondrial oxygen consumption involving inhibition of Complex I activity, which limits the intracellular ROS production under low-oxygen conditions. Thus, reducing mitochondrial Complex I activity via NDUFA4L2 appears to be an essential element in the mitochondrial reprogramming induced by HIF-1. Copyright © 2011 Elsevier Inc. All rights reserved.

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CCDC22 deficiency in humans blunts activation of proinflammatory NF-κB signaling.

Petro Starokadomskyy, Nathan Gluck, Haiying Li … (2013)

NF-κB is a master regulator of inflammation and has been implicated in the pathogenesis of immune disorders and cancer. Its regulation involves a variety of steps, including the controlled degradation of inhibitory IκB proteins. In addition, the inactivation of DNA-bound NF-κB is essential for its regulation. This step requires a factor known as copper metabolism Murr1 domain-containing 1 (COMMD1), the prototype member of a conserved gene family. While COMMD proteins have been linked to the ubiquitination pathway, little else is known about other family members. Here we demonstrate that all COMMD proteins bind to CCDC22, a factor recently implicated in X-linked intellectual disability (XLID). We showed that an XLID-associated CCDC22 mutation decreased CCDC22 protein expression and impaired its binding to COMMD proteins. Moreover, some affected individuals displayed ectodermal dysplasia, a congenital condition that can result from developmental NF-κB blockade. Indeed, patient-derived cells demonstrated impaired NF-κB activation due to decreased IκB ubiquitination and degradation. In addition, we found that COMMD8 acted in conjunction with CCDC22 to direct the degradation of IκB proteins. Taken together, our results indicate that CCDC22 participates in NF-κB activation and that its deficiency leads to decreased IκB turnover in humans, highlighting an important regulatory component of this pathway.

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Author and article information

Contributors

Junfang Zheng

Journal

Journal ID (nlm-ta): PeerJ

Journal ID (iso-abbrev): PeerJ

Journal ID (publisher-id): peerj

Journal ID (pmc): peerj

Title: PeerJ

Publisher: PeerJ Inc. (San Francisco, USA )

ISSN (Electronic): 2167-8359

Publication date (Electronic): 17 November 2017

Publication date Collection: 2017

Volume: 5

Electronic Location Identifier: e4065

Affiliations

[1 ]Department of Urology, Beijing Friendship Hospital, Capital Medical University , Beijing, China

[2 ]Department of Biochemistry and Molecular Biology, Capital Medical University , Beijing, China

[3 ]Core Facilities Center, Capital Medical University , Beijing, China

[4 ]Key Laboratory of Biology of Insect-Pollinator, Ministry of Agriculture, Institute of Apicultural Research, Chinese Academy of Agricultural Sciences , Beijing, China

[5 ]Beijing Key Laboratory for Tumor Invasion and Metastasis, Cancer Institute of Capital Medical University , Beijing, China

Article

Publisher ID: 4065

DOI: 10.7717/peerj.4065

PMC ID: 5695248

SO-VID: 5bed812e-d869-4f2b-826d-c0ba34ab6d98

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

History

Date received : 29 March 2017

Date accepted : 29 October 2017

Funding

Funded by: National Natural Science Foundation of the People’s Republic of China

Award ID: 81372739

Award ID: 81672521

Funded by: Scientific Research Foundation of Beijing Friendship Hospital

Award ID: Yyqdkt2015-14

This work was supported by the National Natural Science Foundation of the People’s Republic of China (No. 81372739, 81672521) and the Scientific Research Foundation of Beijing Friendship Hospital (No. Yyqdkt2015-14). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

NDUFA4L2 is associated with clear cell renal cell carcinoma malignancy and is regulated by ELK1

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Abstract

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Most cited references 20

The mTOR Signalling Pathway in Human Cancer

Induction of the mitochondrial NDUFA4L2 protein by HIF-1α decreases oxygen consumption by inhibiting Complex I activity.

CCDC22 deficiency in humans blunts activation of proinflammatory NF-κB signaling.

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