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Nuclear miR-451a activates KDM7A and leads to cetuximab resistance in head and neck squamous cell carcinoma [miRNA-Seq]

ABSTRACT: Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) during target therapy. Yet the mechanism that caused cetuximab resistance, especially the miRNA regulation therein remains unclear. With growing evidence suggests that miRNAs may function within the cell nucleus and act as “nuclear activating miRNAs” for targeting the promoter region or enhancers related to target genes. They are believed to regulate diseases development including tumorigenesis. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, qRT-PCR and FISH results provide compelling evidence of miR-451a nuclear enrichment with cetuximab treatment. ChIRP-seq, microarray, bioinformatic analysis and dual luciferase reporter assay results show that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It is also demonstrated that activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Analyses of HNSCC samples through logistic regression indicated the significance of miR-451a and KDM7A in cetuximab resistance. These discoveries hold promise for the potential utilization of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear activating miRNAs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE244948 | GEO | 2024/01/01

REPOSITORIES: GEO

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Nuclear miR-451a activates KDM7A and leads to cetuximab resistance in head and neck squamous cell carcinoma [ChIRP-seq]

Project description:Cetuximab resistance has been a major challenge for head and neck squamous cell carcinoma (HNSCC) during target therapy. Yet the mechanism that caused cetuximab resistance, especially the miRNA regulation therein remains unclear. With growing evidence suggests that miRNAs may function within the cell nucleus and act as “nuclear activating miRNAs” for targeting the promoter region or enhancers related to target genes. They are believed to regulate diseases development including tumorigenesis. This study elucidates a novel mechanism underlying cetuximab resistance in HNSCC involving the nuclear activation of KDM7A transcription via miR-451a. Herein, small RNA sequencing, qRT-PCR and FISH results provide compelling evidence of miR-451a nuclear enrichment with cetuximab treatment. ChIRP-seq, microarray, bioinformatic analysis and dual luciferase reporter assay results show that miR-451a interacts with an enhancer region in KDM7A, activating its expression and further facilitating cetuximab resistance. It is also demonstrated that activation of KDM7A by nuclear miR-451a is induced by cetuximab treatment and is AGO2 dependent. Analyses of HNSCC samples through logistic regression indicated the significance of miR-451a and KDM7A in cetuximab resistance. These discoveries hold promise for the potential utilization of miR-451a and KDM7A as valuable biomarkers for cetuximab resistance and emphasize the function of nuclear activating miRNAs.

2024-01-01 | GSE245153 | GEO

Nuclear activating miR-451a induced cetuximab resistance in HNSCC [microarray]

Project description:To filter the up-regulated gene induced by miR-451a overexpression and in cetuximab resistant HNSCC cell. We employed whole genome microarray. The HNSCC cell CAL27 was used as a control sample. CAL27_CTX, the cetuximab resistant CAL27 was compared with CAL27. The miR-451a overexpressed CAL27_451a sample was compared with the CAL27_NC sample. CAL27_CTX and CAL27_451A samples were collected after 48h of cetuximab treatment. The microarray results were taken together with ChIRP-seq analysis and bioinformatics analysis for miR-451a binding and enhancer analysis to eventually find the nuclear acticating target of miR-451a

2024-01-01 | GSE245159 | GEO

Illumina Microarray of MRC5 cell with or without KDM7A-DT overexpression

Project description:KDM7A Divergent Transcript (KDM7A-DT) is a stress-induced lncRNAs. In our previous studies, KDM7A-DT showed the most robust cellular phenotype alteration and a significant TP53-dependency upon oxidative and oncogenic stress induction. To investigate the functional roles of KDM7A-DT, we first performed overexpression experiments using fibroblasts. We found that MRC5 cells overexpressing KDM7A-DT escaped cell cycle proliferation and long-term survival ability and were associated with a distinct stress-related morphology (enlarged and flattened cells) compared to cells expressing just the vehicle control. To examine the effects of KDM7A-DT overexpression on the transcriptome, we performed a differential expression gene (DEG) analysis comparing a group of four independent biological replicates of MRC5 overexpressing KDM7A-DT to a group of samples from control cells.

2023-05-01 | E-MTAB-11819 | biostudies-arrayexpress

Single-cell Sequencing Analysis of Head and Neck Squamous Cell Carcinoma

Project description:To investigate the mechanism of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC), we performed single-cell RNA sequencing analysis in biopsy from two HNSCC patients before and after cetuximab treatment.

2022-04-01 | GSE173647 | GEO

Overcoming cetuximab resistance in HNSCC: The role of AURKB and DUSP proteins

Project description:Unraveling the underlying mechanisms of cetuximab resistance in head and neck squamous cell carcinoma (HNSCC) is of major importance as many tumors remain non-responsive or become resistant. Out microarray results suggest that resistant cells still exhibit RAS-MAPK pathway signaling contributing to drug resistance, as witnessed by low expression of DUSP 5 and DUSP6, negative regulators of ERK1/2, and increased expression of AURKB, a key regulator of mitosis. Therefore, interrupting the RAS-MAPK pathway by an ERK1/2 inhibitor (apigenin) or an AURKB inhibitor (barasertib) might be a new strategy for overcoming cetuximab resistance in HNSCC 4 head and neck squamous cell carcinoma (HNSCC) cell lines were treated with either 15 nM cetuximab or PBS during 13 hours. For each cell line, differential gene expression was assessed between cetuximab and PBS treatments.

2014-09-18 | E-GEOD-61495 | biostudies-arrayexpress

MicroRNA-451a Regulates Myogenesis by Suppressing SPARC Expression Levels

Project description:MicroRNAs (miRNAs) are small noncoding RNAs that critically regulate gene expression. Their abundance and function have been linked to processes such as senescence and aging. In aged monkey muscle, miR-451a and miR-144-3p were highly upregulated compared to young animals. This led us to hypothesize that the miRNAs 451a/144-3p may be involved in muscle differentiation. We found that these miRNAs are downregulated during the differentiation of C2C12 myoblasts. Overexpression of miR-451a, but not miR-144-3p, robustly impeded the differentiation, suggesting an inhibitory role for miR-451a. We further investigated the potential regulatory targets of miR-451a and identified Sparc mRNA, encoding a secreted protein acidic and rich in cysteine (SPARC), which is involved in wound healing and cellular differentiation. Interestingly, we found that miR-451a suppresses Sparc mRNA translation according to the analysis of polysome profile. Our findings show that miR-451a is downregulated in differentiated myoblasts and decreases C2C12 differentiation at least in part by the suppression of SPARC biosynthesis.

2019-04-03 | GSE119186 | GEO

The Lysine Demethylase KDM7A Regulates Immediate Early Genes in Neurons.

Project description:Lysine demethylase KDM7A removes histone modifications H3K9me1/2 and H3K27me1/2. KDM7A plays critical roles in gene expression and contribute to biological processes including tumorigenesis, metabolism, and embryonic development. However, the functions of KDM7A in mammalian nervous system are still poorly explored. In this study, functional roles of KDM7A are comprehensively investigated in neuronal cells by applying CUT&Tag-seq, RNA-seq and mice models. Knockdown of Kdm7a in N2A cells result in the alteration of histone modifications near transcription start sites (TSSs) and the expression changes of a large number of genes. In particular, the expression of immediate early genes (IEGs), a series of genes maintaining the function of the nervous system and associating with neurological disorders, are significantly decreased upon Kdm7a knockdown. Furthermore, in vivo knockdown of Kdm7a in dentate gyrus (DG) neuron of mice hippocampus, via Adeno-associated virus (AAV)-based stereotaxic microinjection, led to a significant decrease of the expression of c-Fos, a marker of neuron activity. Behavior assays in mice further revealed that Kdm7a knockdown in hippocampus repress neuron activity, which leading to impairment of emotion and memory. Collectively, the study reveals that KDM7A affects neuron functions by regulating IEGs, which may provide new clues for understanding epigenetic mechanisms in neurological disorders.

2023-08-21 | GSE232538 | GEO

Vitamin C supplementation reduces expression of circulating miR-451a in poorly controlled type 2 diabetes mellitus

Project description:Four miRNAs showed significantly different expression post-vitamin C supplementation including the down-regulation of miR-451a, and up-regulation of miR-1253, miR-1290 and miR-644a. Subsequent validation study showed only miR-451a expression was significantly different with supplementation.

2020-07-18 | GSE154647 | GEO

The expression profile of Cetuximab resistance in head-and-neck squamous cell carcinoma cells.

Project description:Cetuximab (Erbitux) is an antibody drug against EGFR and commonly used in late stage HNSCC and metastatic colorectal cancer. The oncogenic mutation of certain genes are known to drive Cetuximab resistance such as K-RAS or b-RAF mutation. The aberrant activation of signaling pathways in the presence of Cetuximab treatment to overcome cellular stress contribute to acquired resistance to Cetuximab as well. To better understand the mechanisms and molecular patterns of Cetuximab resistant cells, the Cetuximab resistant cells are trained for examining the gene expression profile. The gene expression array is used for identify the molecular signature governing the Cetuximab resitance.

2017-03-02 | GSE63916 | GEO

Illumina Microarray of T47D cell with or without KDM7A-DT silencing under normal and oxidative stress conditions

Project description:KDM7A Divergent Transcript (KDM7A-DT) is a stress-induced lncRNAs. In our previous studies, KDM7A-DT showed the most robust cellular phenotype alteration and a significant TP53-dependency upon oxidative and oncogenic stress induction. Since about 50% of human breast cancers have mutant p53 and associated genetic alterations, it is essential to determine what effect a mutant p53 would have on acquired pro-oncogenic functions of KDM7A-DT. In these experiments, we used four antisense LNA Gapmer sequences designed by Exiqon (Vedbaek, Denmark). One of these was a negative control, while the other 3 were designed to target the end of the transcript representing the full-length lncRNA KDM7A-DT (lncRNA; GRCh38/hg38, chr7: 140,178,951-140,179,640). To test the effect of KDM7-DT in the context of mutant p53, we selected the p53-negative luminal BC cells T47D. For each of the LNA gapmers, we utilized 3 technical replicates across two main experimental conditions (normal vs. oxidative stress induced via 30 mins of 0.2 mM H2O2 treatment). Overall, we measured the signals for 47,323 Illumina array probes across 24 individual experiments (4 LNA gapmers * 3 technical replicates * 2 main experimental conditions).

2023-05-01 | E-MTAB-11818 | biostudies-arrayexpress

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