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MicroRNA profiling in oesophageal adenocarcinoma cell lines and patient serum samples reveals a role for miR-451a in radiation resistance [control and miR-451a inhibitor treatments]

ABSTRACT: Many patients with Oesophageal Adenocarcinoma (OAC) that undergo chemoradiotherapy do not benefit from treatment due to therapy resistance. We therefore investigated the association of microRNAs, which regulate gene expression, with the response to individual treatments, focusing on radiation, to both better understand the mechanisms involved in resistance and to find potential biomarkers. Intrinsic radiation resistance and chemotherapy drug resistance were assessed in 8 OAC cell lines, and miRNA expression profiling was performed via high throughput qPCR. miRNAs were discovered that were either uniquely associated with resistance to radiation, cisplatin, or 5-FU, or were common to 2 or all 3 of the treatments. Target mRNA pathway analyses indicated several potential mechanisms of treatment resistance. miRNAs associated with the in-vitro treatment responses were then investigated for association with pathologic response to neoadjuvant chemoradiotherapy (nCRT) in pre-treatment serums of 39 patients with OAC. Hsa-miR-451a was associated uniquely with resistance to radiation treatment in the cell lines, and with the response to nCRT in patient serums. Inhibition of hsa-miR-451a in the radiation resistant OAC cell line OE19 increased radiosensitivity (Survival Fraction 73% vs. 87%, p=0.0003), and altered RNA expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE161148 | GEO | 2020/12/15

REPOSITORIES: GEO

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MicroRNA profiling in oesophageal adenocarcinoma cell lines and patient serum samples reveals a role for miR-451a in radiation resistance [miRNA-Seq]

Project description:Many patients with Oesophageal Adenocarcinoma (OAC) that undergo chemoradiotherapy do not benefit from treatment due to therapy resistance. We therefore investigated the association of microRNAs, which regulate gene expression, with the response to individual treatments, focusing on radiation, to both better understand the mechanisms involved in resistance and to find potential biomarkers. Intrinsic radiation resistance and chemotherapy drug resistance were assessed in 8 OAC cell lines, and miRNA expression profiling was performed via high throughput qPCR. miRNAs were discovered that were either uniquely associated with resistance to radiation, cisplatin, or 5-FU, or were common to 2 or all 3 of the treatments. Target mRNA pathway analyses indicated several potential mechanisms of treatment resistance. miRNAs associated with the in-vitro treatment responses were then investigated for association with pathologic response to neoadjuvant chemoradiotherapy (nCRT) in pre-treatment serums of 39 patients with OAC. Hsa-miR-451a was associated uniquely with resistance to radiation treatment in the cell lines, and with the response to nCRT in patient serums. Inhibition of hsa-miR-451a in the radiation resistant OAC cell line OE19 increased radiosensitivity (Survival Fraction 73% vs. 87%, p=0.0003), and altered RNA expression.

2020-12-15 | GSE161088 | GEO

MicroRNA profiling in oesophageal adenocarcinoma cell lines and patient serum samples reveals a role for miR-451a in radiation resistance [patients with Oesophageal Adenocarcinoma]

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Nuclear miR-451a activates KDM7A and leads to cetuximab resistance in head and neck squamous cell carcinoma [miRNA-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 | GSE244948 | GEO

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

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Pre-existing tumoral B cell infiltration and impaired genome maintenance correlate with response to chemoradiotherapy in locally advanced rectal cancer (LARC)

Project description:Using Human Genome 4x44 two-color Agilent microarrays, we established the expression profiling of 39 LARC pretreatment tumor samples to elucidate the molecular features associated with response to treatment after neoadjuvant chemoradiotherapy (nCRT).

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

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Rectal cancer sub-clones respond differentially to neoadjuvant therapy

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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.

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MicroRNA profiling in oesophageal adenocarcinoma cell lines and patient serum samples reveals a role for miR-451a in radiation resistance [control and miR-451a inhibitor treatments]

Project description:MicroRNA profiling in oesophageal adenocarcinoma cell lines and patient serum samples reveals a role for miR-451a in radiation resistance [control and miR-451a inhibitor treatments]

| PRJNA675760 | ENA

Locally advanced rectal cancer transcriptomic-based secretome analysis according to neoadjuvant chemoradiotherapy response

Project description:Most patients with locally advanced rectal cancer (LARC) present incomplete pathological response (pIR) to neoadjuvant chemoradiotherapy (nCRT). Despite the efforts to predict treatment response using tumor-molecular features, as differentially expressed genes, no molecule has proved to be a strong biomarker. The tumor secretome analysis is a promising strategy for biomarkers identification, which can be assessed using transcriptomic data. Here, we performed transcriptomic-based secretome analysis to select potentially secreted proteins using an in silico approach. The tumor expression profile of 28 LARC biopsies carefully selected and collected before nCRT was compared with normal rectal tissues (NT). The expression profile showed no significant differences between cases with complete (pCR) and incomplete response to nCRT. Genes with increased expression (pCR = 106 and pIR = 357) were used for secretome analysis based on public databases (Vesiclepedia, Human Cancer Secretome Database and Plasma and Proteome Database). Seventeen potentially secreted candidates (pCR=1, pIR=13 and 3 in both groups) were further investigated in two independent datasets (TCGA and GSE68204) confirming their over-expression in LARC. The potential secreted biomarkers were also confirmed as associated with the nCRT response (GSE68204). These putative proteins are candidates to be assessed in liquid biopsies aiming a personalized treatment in LARC patients.

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