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MicroRNA Based Liquid Biopsy: The Experience of the Plasma miRNA Signature Classifier MSC for Lung Cancer Screening
Published on: October 26, 2017
MicroRNA expression profiling and biomarker validation in treatment-naïve and drug resistant non-small cell lung
Lauren MacDonagh1, Michael F Gallagher2, Brendan Ffrench2
1Thoracic Oncology Research Group, School of Medicine, Trinity Translational Medicine Institute, Trinity Centre for Health Sciences, St. James's Hospital and Trinity College Dublin, Dublin, Ireland.
Background:
In the absence of targetable mutations or immune checkpoints, cisplatin-doublet chemotherapy remains the standard of care in non-small cell lung cancer (NSCLC). Drug resistance has however become a significant clinical challenge. Exploring a role for small non-coding microRNAs (miRNA) as biomarker candidates in cisplatin resistant (CisR) lung cancer is lacking and warrants further investigation.
Methods:
miRNA expression profiling was assessed in a panel of cisplatin sensitive and resistant NSCLC cell lines and validated by qPCR. Modulation of altered miRNAs was studied using antagomiRs and pre-miRs while functional assays were used to assess cisplatin response. The translational relevance of these miRNAs as potential biomarkers was assessed in serum and matched normal and tumour lung tissues from chemo-naïve NSCLC patients, in addition to xenograft formalin-fixed paraffin-embedded (FFPE) tumours derived from cisplatin sensitive and resistant cell lines.
Results:
Differential expression of a 5-miR signature (miR-30a-3p, miR-30b-5p, miR-30c-5p, miR-34a-5p, miR-4286) demonstrated their ability to distinguish between normal and tumour lung tissue and between NSCLC histologies. In squamous cell carcinoma (SqCC), tissue miRNA expression was associated with poor survival. miR-4286 showed promise as a blood-based diagnostic biomarker that could distinguish between adenocarcinoma and SqCC histologies. In a xenograft model of cisplatin resistance, using 7-9 week old female NOD/SCID mice (NOD.CB17-Prkdcscid/NCrCrl), a 5-miRNA panel showed altered expression between sensitive and resistant tumours.
Conclusions:
This study identified a panel of miRNAs which may have diagnostic and prognostic potential as novel biomarkers in lung cancer and furthermore, may have a predictive role in monitoring the emergence of resistance to cisplatin.
Insights
This study identifies a panel of five microRNAs (miRNAs) that can distinguish between lung cancer tissues and normal tissues, and may serve as biomarkers for predicting cisplatin resistance in non-small cell lung cancer (NSCLC). These miRNAs also show potential for diagnosing different NSCLC subtypes.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Discovery
Background:
- Cisplatin-doublet chemotherapy is standard for non-small cell lung cancer (NSCLC) lacking targetable mutations.
- Drug resistance to cisplatin presents a significant clinical challenge in NSCLC treatment.
- The role of microRNAs (miRNAs) as biomarkers for cisplatin resistance in NSCLC requires further investigation.
Purpose of the Study:
- To identify microRNA (miRNA) signatures associated with cisplatin sensitivity and resistance in non-small cell lung cancer (NSCLC).
- To evaluate the diagnostic and prognostic potential of identified miRNAs in NSCLC patients.
- To explore the translational relevance of miRNAs as biomarkers in patient samples and preclinical models.
Main Methods:
- miRNA expression profiling in cisplatin-sensitive and resistant NSCLC cell lines, validated by qPCR.
- Modulation of miRNA expression using antagomiRs and pre-miRs to assess functional impact on cisplatin response.
- Analysis of miRNA expression in patient serum, lung tissues, and FFPE xenograft tumors.
Main Results:
- A 5-miRNA signature (miR-30a-3p, miR-30b-5p, miR-30c-5p, miR-34a-5p, miR-4286) differentiated normal lung tissue from tumors and NSCLC histologies.
- Squamous cell carcinoma (SqCC) miRNA expression correlated with poor survival.
- miR-4286 demonstrated potential as a blood-based biomarker for distinguishing adenocarcinoma from SqCC.
- Altered expression of the 5-miRNA panel was observed in cisplatin-resistant xenograft tumors.
Conclusions:
- A panel of miRNAs has diagnostic and prognostic potential as novel biomarkers in lung cancer.
- These miRNAs may serve as predictive biomarkers for monitoring the development of cisplatin resistance.
- Further research into these miRNA signatures could improve NSCLC patient management and treatment strategies.
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