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

Wang, Decai; Zhang, Pu; Liu, Zijian; Xing, Yifei; Xiao, Yajun

doi:10.3390/cancers14153782

Cited by 12 publications

(19 citation statements)

References 41 publications

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“…Our identification of the hypermethylation of some endocrine related genes, neuroexophilin-4 ( nxph4 ) and thyroid hormone receptor interacting protein-12 ( trip12 ), is relevant to the emerging concept that ALS is a metabolic syndrome [ 45 , 47 , 48 , 49 ]. Nxph4 is a secreted neuropeptide-like glycoprotein and a positive regulator of glycolysis and mitochondrial complex I [ 105 ]. Trip12 has many functions, including DNA damage and repair, chromatin remodeling, and muscle fiber selective proteasomal degradation of the multifaceted transcription factor Sox-6 [ 106 , 107 ].…”

Section: Discussionmentioning

confidence: 99%

Aberrant DNA and RNA Methylation Occur in Spinal Cord and Skeletal Muscle of Human SOD1 Mouse Models of ALS and in Human ALS: Targeting DNA Methylation Is Therapeutic

Martin

Adams

Niedzwiecki

et al. 2022

Cells

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Amyotrophic lateral sclerosis (ALS) is a fatal disease. Skeletal muscles and motor neurons (MNs) degenerate. ALS is a complex disease involving many genes in multiple tissues, the environment, cellular metabolism, and lifestyles. We hypothesized that epigenetic anomalies in DNA and RNA occur in ALS and examined this idea in: (1) mouse models of ALS, (2) human ALS, and (3) mouse ALS with therapeutic targeting of DNA methylation. Human superoxide dismutase-1 (hSOD1) transgenic (tg) mice were used. They expressed nonconditionally wildtype (WT) and the G93A and G37R mutant variants or skeletal muscle-restricted WT and G93A and G37R mutated forms. Age-matched non-tg mice were controls. hSOD1 mutant mice had increased DNA methyltransferase enzyme activity in spinal cord and skeletal muscle and increased 5-methylcytosine (5mC) levels. Genome-wide promoter CpG DNA methylation profiling in skeletal muscle of ALS mice identified hypermethylation notably in cytoskeletal genes. 5mC accumulated in spinal cord MNs and skeletal muscle satellite cells in mice. Significant increases in DNA methyltransferase-1 (DNMT1) and DNA methyltransferase-3A (DNMT3A) levels occurred in spinal cord nuclear and chromatin bound extracts of the different hSOD1 mouse lines. Mutant hSOD1 interacted with DNMT3A in skeletal muscle. 6-methyladenosine (6mA) RNA methylation was markedly increased or decreased in mouse spinal cord depending on hSOD1-G93A model, while fat mass and obesity associated protein was depleted and methyltransferase-like protein 3 was increased in spinal cord and skeletal muscle. Human ALS spinal cord had increased numbers of MNs and interneurons with nuclear 5mC, motor cortex had increased 5mC-positive neurons, while 6mA was severely depleted. Treatment of hSOD1-G93A mice with DNMT inhibitor improved motor function and extended lifespan by 25%. We conclude that DNA and RNA epigenetic anomalies are prominent in mouse and human ALS and are potentially targetable for disease-modifying therapeutics.

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Section: Discussionmentioning

confidence: 99%

Aberrant DNA and RNA Methylation Occur in Spinal Cord and Skeletal Muscle of Human SOD1 Mouse Models of ALS and in Human ALS: Targeting DNA Methylation Is Therapeutic

Martin

Adams

Niedzwiecki

et al. 2022

Cells

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“…This mitochondrial complex I inhibitor was identified to be overexpressed in colorectal cancer (CRC) tissues and that is associated with tumor progression and poor prognosis ( 35 ). A prior study showed that NXPH4 can enhance cancer cell proliferation and invasion by modulating NDUFA4L2 in bladder cancer ( 13 ). To the other co-expressed genes, the hydroxymethyltransferase 2 (SHMT2) was reported as key regulators in the serine metabolism pathway and is involved in colon cancer proliferation ( 36 ).…”

Section: Discussionmentioning

confidence: 99%

“…Hypoxia shapes the landscape of the TME that contributes to tumor plasticity and heterogeneity and promotes highly aggressive and metastatic phenotypes ( 50 ). A previous study also showed that NXPH4 expression can promote reactive oxygen species (ROS) and glycolysis activation through modulating NDUFA4L2 to enhance gemcitabine resistance in bladder cancer cells ( 13 ). Another recent study reported that knockdown of NXPH4 was shown to inhibit cell proliferation, migration, and glycolysis in CRC cells ( 51 ).…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, recent studies have also implicated NXPH4 in the development and progression of several malignant tumors including bladder cancer ( 11 - 13 ), hepatocellular carcinoma ( 14 , 15 ), and non-small cell lung cancer ( 16 ). Additionally, it was reported that NXPH4 promotes gemcitabine resistance in bladder cancer ( 13 ). However, the biological functions, clinical significance, and underlying molecular mechanisms of NXPH4 in COAD remain largely unknown and unexplored.…”

Section: Introductionmentioning

confidence: 99%

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High expression of NXPH4 correlates with poor prognosis, metabolic reprogramming, and immune infiltration in colon adenocarcinoma

Sun,

Wang,

et al. 2024

J Gastrointest Oncol

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Background Colon adenocarcinoma (COAD) is a prevalent gastrointestinal malignant disease with high mortality rate, and identification of novel prognostic biomarkers and therapeutic targets is urgently needed. Although neurexophilin 4 (NXPH4) has been investigated in several tumors, its role in COAD remains unclear. The aim of this study was to explore the prognostic value and potential functions of NXPH4 in COAD. Methods The expression of NXPH4 in COAD were analyzed using The Cancer Genome Atlas (TCGA) and datasets from the Gene Expression Omnibus (GEO) database. The prognostic value of NXPH4 was determined using Kaplan-Meier analysis and Cox regression analysis. To investigate the possible mechanism underlying the role of NXPH4 in COAD, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and gene set enrichment analysis (GSEA) were employed. The correlation between NXPH4 expression and immune cell infiltration levels was examined thorough single-sample gene set enrichment analysis (ssGSEA). Furthermore, the competing endogenous RNA (ceRNA) regulatory network that may be involved in NXPH4 in COAD was predicted and constructed through a variety of databases. Results NXPH4 expression was significantly higher in COAD tissue compared with normal colon tissues. Meanwhile, high expression of NXPH4 was associated with poor prognosis in COAD patients. GO-KEGG and GSEA analyses indicated that NXPH4 was associated with glycolysis and hypoxia pathway, and may promote COAD progression and metastasis by modulating metabolic reprogramming. ssGSEA analysis demonstrated that NXPH4 expression also associated with immune infiltration. Furthermore, we identified various microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) as upstream regulators of NXPH4 in COAD. Conclusions The present study revealed that high expression of NXPH4 is associated with tumor progression, metabolic reprogramming, and immune infiltration. These findings suggest that NXPH4 could serve as a reliable prognostic biomarker and a promising therapeutic target in COAD.

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“…Neurexophilin4 (NXPH4) is a neuro synaptic secretory protein. It is an essential neuropeptide-like glycoprotein that belongs to the neurophilic rexophilin family [ 12 ]. NXPH4 promotes cancer cell proliferation, migration, and invasion and is vital in the tumor metastasis cascade [ 12 ].…”

Section: Introductionmentioning

confidence: 99%

NXPH4 can be used as a biomarker for pan-cancer and promotes colon cancer progression

Zhang,

Wang,

Chen

et al. 2024

Aging

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NXPH4 promotes cancer proliferation and invasion. However, its specific role and mechanism in cancer remain unclear. Transcriptome and clinical data for pan-cancer were derived from the TCGA database. K-M survival curve and univariate Cox were used for prognostic analysis. CIBERSORT and TIMER algorithms were employed to calculate immune cell infiltration. Gene set enrichment analysis (GSEA) was employed for investigating the function of NXPH4. Western blot verified differential expression of NXPH4 in colon cancer. Functional assays (CCK-8, plate clonogenicity assay, wound healing assay, and Transwell assay) confirmed the impact of NXPH4 on proliferation, invasion, and migration of colon cancer cells. Dysregulation of NXPH4 in pan-cancer suggests its potential as a diagnostic and prognostic marker for certain cancers, including colon and liver cancer. High expression of NXPH4 in pan-cancer might be associated with the increase in copy number and hypomethylation. NXPH4 expression in pan-cancer is substantially linked to immune cell infiltration in the immune microenvironment. NXPH4 expression is associated with the susceptibility to immunotherapy and chemotherapy. Western blot further confirmed the higher expression of NXPH4 in colon cancer. Knockdown of NXPH4 significantly suppresses proliferation, invasion, and migration of colon cancer cell lines HT-29 and HCT116, as validated by functional assays.

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

Cited by 12 publications

References 41 publications

Aberrant DNA and RNA Methylation Occur in Spinal Cord and Skeletal Muscle of Human SOD1 Mouse Models of ALS and in Human ALS: Targeting DNA Methylation Is Therapeutic

Aberrant DNA and RNA Methylation Occur in Spinal Cord and Skeletal Muscle of Human SOD1 Mouse Models of ALS and in Human ALS: Targeting DNA Methylation Is Therapeutic

High expression of NXPH4 correlates with poor prognosis, metabolic reprogramming, and immune infiltration in colon adenocarcinoma

NXPH4 can be used as a biomarker for pan-cancer and promotes colon cancer progression

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