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MicroRNA Profiling in Oesophageal Adenocarcinoma Cell Lines and Patient Serum Samples Reveals a Role for miR-451a in
Frederike Butz1,2, Ann-Kathrin Eichelmann1,3, George C Mayne1,4
1Flinders Health and Medical Research Institute-Cancer Program, Flinders University, Bedford Park, SA 5042, Australia.
Abstract:
Many patients with Oesophageal Adenocarcinoma (OAC) do not benefit from chemoradiotherapy treatment due to therapy resistance. To better understand the mechanisms involved in resistance and to find potential biomarkers, we investigated the association of microRNAs, which regulate gene expression, with the response to individual treatments, focusing on radiation. Intrinsic radiation resistance and chemotherapy drug resistance were assessed in eight OAC cell lines, and miRNA expression profiling was performed via TaqMan OpenArray qPCR. miRNAs discovered were either uniquely associated with resistance to radiation, cisplatin, or 5-FU, or were common to two or all three 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 patients with OAC. 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 miR-451a in the radiation resistant OAC cell line OE19 increased radiosensitivity (Survival Fraction 73% vs. 87%, p = 0.0003), and altered RNA expression. Pathway analysis of effected small non-coding RNAs and corresponding mRNA targets suggest potential mechanisms of radiation resistance in OAC.
Insights
MicroRNAs (miRNAs) are key to understanding oesophageal adenocarcinoma (OAC) treatment resistance. miR-451a is linked to radiation resistance and patient response, offering potential therapeutic targets.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Oesophageal adenocarcinoma (OAC) patients often exhibit resistance to chemoradiotherapy.
- Understanding resistance mechanisms is crucial for improving treatment efficacy.
- MicroRNAs (miRNAs) play a role in regulating gene expression and may influence treatment response.
Purpose of the Study:
- To investigate the association of miRNAs with resistance to radiation and chemotherapy in OAC.
- To identify potential miRNA biomarkers for predicting response to chemoradiotherapy.
- To explore mechanisms of treatment resistance mediated by miRNAs.
Main Methods:
- Assessed intrinsic radiation and chemotherapy drug resistance in eight OAC cell lines.
- Performed miRNA expression profiling using TaqMan OpenArray qPCR.
- Investigated miRNA associations with in vitro treatment responses and patient serum samples.
Main Results:
- Identified miRNAs uniquely or commonly associated with resistance to radiation, cisplatin, or 5-FU.
- miR-451a was uniquely associated with radiation resistance in cell lines and nCRT response in patients.
- Inhibition of miR-451a increased radiosensitivity in an OAC cell line.
Conclusions:
- miR-451a is a potential biomarker for predicting response to chemoradiotherapy in OAC.
- Targeting miR-451a may represent a therapeutic strategy to overcome radiation resistance.
- miRNAs and their target pathways offer insights into OAC treatment resistance mechanisms.
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