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Multi-comparative Bioinformatic Detection of MEOX2 De Novo Motif Sites And Distal Intergenic Sequences By ChIP-Seq, Reveals MEOX2-Dependent Modulation of EGFR-Gene Sequences In A Lung Cancer Preclinical Model

ABSTRACT: Mesenchyme Homebox-2 (MEOX2) transcription factor and its role in lung malignant diseases. It is mentioned that MEOX2 has recently been proposed as a genetically amplified and overexpressed lung tumor biomarker that promotes cellular proliferation, tumor growth, pre- and clinical progression, and oncological therapy resistance. The study used a large-scale epigenome occupancy strategy to identify novel MEOX2-related cellular pathways. It was also discovered that MEOX2 has a significant occupation on distal intergenic sequences, De Novo Moitf Sites as well as on EGFR-genetic sequences, and positively regulates EGFR-gene expression in human lung cancer cells and preclinical tumor growth. The study concluded that overexpressed MEOX2 is negatively clinically correlated with poorer progression-free survival in lung cancer patients with early clinical stages, with or without EGFR-TKIs based therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE230567 | GEO | 2023/06/15

REPOSITORIES: GEO

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Project description:Lung cancer is the leading cause of death from malignant diseases worldwide, with the non-small cell (NSCLC) subtype accounting for the majority of cases. NSCLC is characterized by frequent genomic imbalances and copy number variations (CNVs), but the epigenetic aberrations that are associated with clinical prognosis and therapeutic failure remain not completely identify. In the present study, a total of 55 lung cancer patients were included and we conducted genomic and genetic expression analyses, immunohistochemical protein detection, DNA methylation and chromatin immunoprecipitation assays to obtain genetic and epigenetic profiles associated to prognosis and chemoresponse of NSCLC patients. Finally, siRNA transfection-mediated genetic silencing and cisplatinum cellular cytotoxicity assays in NSCLC cell lines A-427 and INER-37 were assesed to described chemoresistance mechanisms involved. Our results identified high frequencies of CNVs (60% of cases) in the 7p22.3-p21.1 and 7p15.3-p15.2 cytogenetic regions. However, overexpression of genes, such as MEOX2, HDAC9, TWIST1 and AhR, at 7p21.2-p21.1 locus occurred despite the absence of CNVs and little changes in DNA methylation. In contrast, the promoter sequences of MEOX2 and TWIST1 displayed significantly lower/decrease in the repressive histone mark H3K27me3 and increased in the active histone mark H3K4me3 levels. Finally these results correlate with poor survival in NSCLC patients and cellular chemoresistance to oncologic drugs in NSCLC cell lines in a MEOX2 and TWIST1 overexpression dependent-manner. In conclusion, we report for the first time that MEOX2 participates in chemoresistance irrespective of high CNV, but it is significantly dependent upon H3K27me3 enrichment probably associated with aggressiveness and chemotherapy failure in NSCLC patients, however additional clinical studies must be performed to confirm our findings as new probable clinical markers in NSCLC patients. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from fresh frozen, and paraffin embedded lung tumor samples Copy number analysis of Affymetrix 500K SNP arrays was performed for 33 lung tumor samples, including lung precursor metaplasia, lung tumors and cell lines. Six samples were also hybridized on the Affymetrix SNP 6.0 array

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Multi-comparative Bioinformatic Detection of MEOX2 De Novo Motif Sites And Distal Intergenic Sequences By ChIP-Seq, Reveals MEOX2-Dependent Modulation of EGFR-Gene Sequences In A Lung Cancer Preclinical Model

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