Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma

Laursen, Kristian B.; Khani, Francesca; Attarwala, Nabeel; Groß, Steven; Dow, Lukas E.; Nanus, David M.; Gudas, Lorraine J.

doi:10.3389/fonc.2021.783856

Cited by 8 publications

(7 citation statements)

References 47 publications

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“…NDUFA4L2 has been widely reported to induce glycolysis [ 35 , 36 , 37 , 38 , 39 ]. We found elevated protein levels of NDUFA4L2 in both T24GEM-R and 5637GEM-R. After the overexpression and knockdown of NXPH4 in T24GEM-R and 5637GEM-R, we found associated upregulation and downregulation of NDUFA4L2, respectively, indicating that NXPH4 may function through the regulation of NDUFA4L2.…”

Section: Discussionmentioning

confidence: 99%

“…We found elevated protein levels of NDUFA4L2 in both T24GEM-R and 5637GEM-R. After the overexpression and knockdown of NXPH4 in T24GEM-R and 5637GEM-R, we found associated upregulation and downregulation of NDUFA4L2, respectively, indicating that NXPH4 may function through the regulation of NDUFA4L2. VHL, PKM2, GLUT1, and HK2 are crucial target genes for NDUFA4L2 [ 39 ] and are responsible for a series of biological processes such as cell survival and apoptosis [ 40 ]. In order to confirm our hypothesis, we detected the protein levels of these genes after NXPH4 knockdown.…”

Section: Discussionmentioning

confidence: 99%

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NXPH4 Promotes Gemcitabine Resistance in Bladder Cancer by Enhancing Reactive Oxygen Species and Glycolysis Activation through Modulating NDUFA4L2

Wang

Zhang

Liu

et al. 2022

Cancers

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Bladder cancer is one of the most prevalent kinds of cancer worldwide, and resistance to gemcitabine is a major problem for patients. The pathogenesis of bladder cancer and mechanism of resistance to chemotherapy remain to be explored. Through bioinformatics analysis, we first found that NXPH4 was independently related to the prognosis of patients with bladder cancer. Through wound healing assays, transwell invasion assays, and plate clone formation assays, we found that NXPH4 promoted the proliferation, migration, and invasion of bladder cancer cells. The induced gemcitabine resistance cell line also showed a higher expression of NXPH4. A glycolytic activity assay demonstrated that the expression of NXPH4 was positively related to glycolysis. A higher level of reactive oxygen species caused by enhanced levels of NXPH4 was found in gemcitabine-resistant cell lines. NDUFA4L2, glycolysis, and reactive oxygen species were shown to be essential for NXPH4-regulated functions through rescue assays in cell lines. The roles of NXPH4-regulated glycolysis, gemcitabine resistance, and NDUFA4L2 were validated in vivo as well. Our results imply that NXPH4 contributes to the proliferation, migration, and invasion of bladder cancer by maintaining the stability of NDUFA4L2 and consequently activating reactive oxygen species and glycolysis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

NXPH4 Promotes Gemcitabine Resistance in Bladder Cancer by Enhancing Reactive Oxygen Species and Glycolysis Activation through Modulating NDUFA4L2

Wang

Zhang

Liu

et al. 2022

Cancers

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“…Immunostaining and Hematoxylin/Eosin (H&E) staining of the mouse kidney cortex sections was performed as previously described 29 , 30 . In brief, paraformaldehyde-fixed kidney sections were cut to 7 μm and mounted on glass slides by the Cornell Core Facility.…”

Section: Methodsmentioning

confidence: 99%

Novel genetically engineered mouse models for clear cell renal cell carcinoma

Mijn

Laursen

et al. 2023

Sci Rep

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Genetically engineered mouse models (GEMMs) are important immunocompetent models for research into the roles of individual genes in cancer and the development of novel therapies. Here we use inducible CRISPR-Cas9 systems to develop two GEMMs which aim to model the extensive chromosome p3 deletion frequently observed in clear cell renal cell carcinoma (ccRCC). We cloned paired guide RNAs targeting early exons of Bap1, Pbrm1, and Setd2 in a construct containing a Cas9D10A (nickase, hSpCsn1n) driven by tetracycline (tet)-responsive elements (TRE3G) to develop our first GEMM. The founder mouse was crossed with two previously established transgenic lines, one carrying the tet-transactivator (tTA, Tet-Off) and one with a triple-mutant stabilized HIF1A-M3 (TRAnsgenic Cancer of the Kidney, TRACK), both driven by a truncated, proximal tubule-specific γ-glutamyltransferase 1 (ggt or γGT) promoter, to create triple-transgenic animals. Our results indicate that this model (BPS-TA) induces low numbers of somatic mutations in Bap1 and Pbrm1 (but not in Setd2), known tumor suppressor genes in human ccRCC. These mutations, largely restricted to kidneys and testis, induced no detectable tissue transformation in a cohort of 13 month old mice (N = 10). To gain insights into the low frequencies of insertions and deletions (indels) in BPS-TA mice we analyzed wild type (WT, N = 7) and BPS-TA (N = 4) kidneys by RNAseq. This showed activation of both DNA damage and immune response, suggesting activation of tumor suppressive mechanisms in response to genome editing. We then modified our approach by generating a second model in which a ggt-driven, cre-regulated Cas9WT(hSpCsn1) was employed to introduce Bap1, Pbrm1, and Setd2 genome edits in the TRACK line (BPS-Cre). The BPS-TA and BPS-Cre lines are both tightly controlled in a spatiotemporal manner with doxycycline (dox) and tamoxifen (tam), respectively. In addition, whereas the BPS-TA line relies on paired guide RNAs (gRNAs), the BPS-Cre line requires only single gRNAs for gene perturbation. In the BPS-Cre we identified increased Pbrm1 gene-editing frequencies compared to the BPS-TA model. Whereas we did not detect Setd2 edits in the BPS-TA kidneys, we found extensive editing of Setd2 in the BPS-Cre model. Bap1 editing efficiencies were comparable between the two models. Although no gross malignancies were observed in our study, this is the first reported GEMM which models the extensive chromosome 3p deletion frequently observed in kidney cancer patients. Further studies are required (1) to model more extensive 3p deletions, e.g. impacting additional genes, and (2) to increase the cellular resolution, e.g. by employing single-cell RNAseq to ascertain the effects of specific combinatorial gene inactivation.

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“…NDUFA4L2 also increases the expression of carbonic anhydrase 9, a marker of ccRCC, [13] and promotes the deposition of lipids in a murine ccRCC model. [14] Hence, in this research, we used the CRC RNA-seq data in TCGA database to compare the difference of NDUFA4L2 expression between tumor tissues and normal samples, and investigated the correlation between NDUFA4L2 expression levels and clinical pathological features of CRC. Next, we evaluated the prognostic value of NDUFA4L2 in CRC.…”

Section: Introductionmentioning

confidence: 99%

“…NDUFA4L2 also increases the expression of carbonic anhydrase 9, a marker of ccRCC, [ 13 ] and promotes the deposition of lipids in a murine ccRCC model. [ 14 ]…”

Section: Introductionmentioning

confidence: 99%

NDUFA4L2 is a novel biomarker for colorectal cancer through bioinformatics analysis

Lin,

Xie,

Zhao

et al. 2023

Medicine

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Colorectal cancer (CRC) is a major cause of cancer-related deaths worldwide. NDUFAL42 is an important mitochondrial respiratory chain subunit that plays a critical role in cellular energy metabolism. However, the role of NDUFA4L2 in CRC remains unclear. Therefore, we used the data obtained from The Cancer Genome Atlas (TCGA) database to prove the relationship between NDUFA4L2 and CRC. The expression levels of NDUFA4L2 in CRC tissues were analyzed by immunohistochemical staining of NDUFA4L2 from the HPA database. Wilcoxon rank sum test, Chi-square test, Fisher exact test and logistic regression were used to evaluate relationships between clinical-pathologic features and NDUFA4L2 expression. Receiver operating characteristic (ROC) curves were used to describe binary classifier value of NDUFA4L2 using area under curve (AUC) score. Kaplan–Meier method and Cox regression analysis were used to evaluate factors contributing to prognosis. Gene oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used to predict the function of differentially expressed genes associated with NDUFA4L2. Gene set enrichment analysis (GSEA) was used to predict canonical pathways associated with NDUFA4L2.Immune infiltration analysis was performed to identify the significantly involved functions of NDUFA4L2. Protein–protein interaction (PPI) networks were established and 20 hub genes identified with Cytoscape software. Increased NDUFA4L2 expression in CRC was associated with T stage (P = .019), N stage (P < .001), Pathologic stage (P = .020), Residual tumor (P = .023), Perineural invasion (P = .039), Lymphatic invasion (P = .007), Histological type(P < .001), PFI event (P = .007) and DSS event (P = .004).ROC curve suggested the significant diagnostic and prognostic ability of NDUFA4L2 (AUC = 0.878). High NDUFA4L2 expression predicted a poorer Overall-survival (P = .021), poorer progression-free interval (P = .001), and poorer Disease Specific Survival (P = .002). GO, KEGG, GSEA and immune infiltration analysis showed that NDUFA4L2 expression was correlated with regulating the function of DNA and some types of immune infiltrating cells. NDUFA4L2 expression was significantly correlated with poor survival and immune infiltrations in CRC, and it may be a promising prognostic biomarker in CRC.

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Mitochondrial Ndufa4l2 Enhances Deposition of Lipids and Expression of Ca9 in the TRACK Model of Early Clear Cell Renal Cell Carcinoma

Cited by 8 publications

References 47 publications

NXPH4 Promotes Gemcitabine Resistance in Bladder Cancer by Enhancing Reactive Oxygen Species and Glycolysis Activation through Modulating NDUFA4L2

NXPH4 Promotes Gemcitabine Resistance in Bladder Cancer by Enhancing Reactive Oxygen Species and Glycolysis Activation through Modulating NDUFA4L2

Novel genetically engineered mouse models for clear cell renal cell carcinoma

NDUFA4L2 is a novel biomarker for colorectal cancer through bioinformatics analysis

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