Evaluation of the Diagnostic and Prognostic Potential, and Correlation with the Tumor Immune Microenvironment of a Six-miRNA Signature Associated with Platinum Sensitivity in Patients with Early-Stage Non-Small-Cell Lung Cancer
4 affiliations
- 1Laboratory of Translational Oncology, School of Medicine, University of Crete, 71500 Heraklion, Greece
- 2Department of Medical Oncology, University General Hospital of Heraklion, 71500 Heraklion, Greece
- 3Department of Pathology, University General Hospital of Heraklion, 71500 Heraklion, Greece
- 4School of Medicine, University of Crete, 70013 Heraklion, Greece
Abstract
Background/Objectives: Platinum-based chemotherapy remains a standard-of-care treatment for non-small-cell lung cancer (NSCLC), yet its efficacy is influenced by multiple factors, such as the functionality of DNA damage response pathways. DNA-damaging agents, like cisplatin, contribute to the generation of an “inflamed” tumor microenvironment (TME), which in turn correlates with an active antitumor immune response. MicroRNAs (miRNAs), a family of small, non-coding RNAs, have emerged as critical post-transcriptional regulators of gene expression, playing vital roles in modulating DNA Damage Repair (DDR) pathways and sensitivity to cisplatin. Their functional involvement in these mechanisms underscores their potential as diagnostic and prognostic biomarkers in lung cancer. Methods: In this study, we investigated the diagnostic and prognostic value of a previously validated six-miRNA signature (hsa-miR-26a, hsa-miR-29c, hsa-miR-34a, hsa-miR-30-5p, hsa-miR-30e-3p and hsa-miR-497) in paired tumor and healthy tissue samples from surgically treated NSCLC patients (n = 76), who later received platinum-based therapy. To explore the translational applicability of this signature, we also compared miRNA expression levels between matched tumor tissue and plasma samples (n = 36). We further examined the presence of an “inflamed” TME and its association with the miRNA signature by examining the mRNA levels of TIGIT, CD8A, FOXP3, CXCL10 and PD-L1, and performing correlation analysis. Results: All selected miRNAs were significantly downregulated in NSCLC tumor tissue compared to healthy samples. Moreover, miRNA expression was differentially regulated in plasma samples, supporting their potential clinical relevance as minimally invasive biomarkers. The complete six-miRNA signature demonstrated good discriminatory ability between tumor and matched non-malignant tissue (AUC = 0.786, 95% CI: 0.713–0.860; p < 0.001), with 72% sensitivity and 77.3% specificity. A significant correlation with relapse-free survival (RFS) (p = 0.039) was also observed. Distinct immune-related transcriptional alterations were observed in tumor tissue, including increased expression of immune checkpoint-associated genes (TIGIT and PD-L1) and reduced CD8A expression. Tumor PD-L1 expression showed modest positive correlations with miR-26a (p = 0.046) and miR-30e-3p (p = 0.031). Conclusions: Our findings underscore the potential value of this novel six-miRNA signature both as a prognostic and diagnostic biomarker in NSCLC. Its correlation with immune microenvironment characteristics supports its relevance in guiding personalized therapeutic strategies. This signature warrants further clinical validation and may serve as a valuable tool for patient stratification and outcome prediction for patients treated with platinum-based chemotherapy.
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BibTeX
@article{mortoglou2026evaluation,
title = {{Evaluation of the Diagnostic and Prognostic Potential, and Correlation with the Tumor Immune Microenvironment of a Six-miRNA Signature Associated with Platinum Sensitivity in Patients with Early-Stage Non-Small-Cell Lung Cancer}},
author = {Maria Mortoglou and Chara Papadaki and Aristeidis E. Boukouris and Kleita Michaelidou and Eleftherios Vorrias and Maria Kamaratou and Georgios Koronakis and Eleni Lagoudaki and Anastasios Koutsopoulos and Dimitrios Mavroudis and Sofia Agelaki},
journal = {Cancers},
year = {2026},
month = oct,
doi = {10.3390/cancers18203351},
url = {https://www.mdpi.com/2072-6694/18/20/3351},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Evaluation of the Diagnostic and Prognostic Potential, and Correlation with the Tumor Immune Microenvironment of a Six-miRNA Signature Associated with Platinum Sensitivity in Patients with Early-Stage Non-Small-Cell Lung Cancer
AU - Maria Mortoglou
AU - Chara Papadaki
AU - Aristeidis E. Boukouris
AU - Kleita Michaelidou
AU - Eleftherios Vorrias
AU - Maria Kamaratou
AU - Georgios Koronakis
AU - Eleni Lagoudaki
AU - Anastasios Koutsopoulos
AU - Dimitrios Mavroudis
AU - Sofia Agelaki
PY - 2026
DA - 2026/10/01
JO - Cancers
DO - 10.3390/cancers18203351
UR - https://www.mdpi.com/2072-6694/18/20/3351
AB - Background/Objectives: Platinum-based chemotherapy remains a standard-of-care treatment for non-small-cell lung cancer (NSCLC), yet its efficacy is influenced by multiple factors, such as the functionality of DNA damage response pathways. DNA-damaging agents, like cisplatin, contribute to the generation of an “inflamed” tumor microenvironment (TME), which in turn correlates with an active antitumor immune response. MicroRNAs (miRNAs), a family of small, non-coding RNAs, have emerged as critical post-transcriptional regulators of gene expression, playing vital roles in modulating DNA Damage Repair (DDR) pathways and sensitivity to cisplatin. Their functional involvement in these mechanisms underscores their potential as diagnostic and prognostic biomarkers in lung cancer. Methods: In this study, we investigated the diagnostic and prognostic value of a previously validated six-miRNA signature (hsa-miR-26a, hsa-miR-29c, hsa-miR-34a, hsa-miR-30-5p, hsa-miR-30e-3p and hsa-miR-497) in paired tumor and healthy tissue samples from surgically treated NSCLC patients (n = 76), who later received platinum-based therapy. To explore the translational applicability of this signature, we also compared miRNA expression levels between matched tumor tissue and plasma samples (n = 36). We further examined the presence of an “inflamed” TME and its association with the miRNA signature by examining the mRNA levels of TIGIT, CD8A, FOXP3, CXCL10 and PD-L1, and performing correlation analysis. Results: All selected miRNAs were significantly downregulated in NSCLC tumor tissue compared to healthy samples. Moreover, miRNA expression was differentially regulated in plasma samples, supporting their potential clinical relevance as minimally invasive biomarkers. The complete six-miRNA signature demonstrated good discriminatory ability between tumor and matched non-malignant tissue (AUC = 0.786, 95% CI: 0.713–0.860; p < 0.001), with 72% sensitivity and 77.3% specificity. A significant correlation with relapse-free survival (RFS) (p = 0.039) was also observed. Distinct immune-related transcriptional alterations were observed in tumor tissue, including increased expression of immune checkpoint-associated genes (TIGIT and PD-L1) and reduced CD8A expression. Tumor PD-L1 expression showed modest positive correlations with miR-26a (p = 0.046) and miR-30e-3p (p = 0.031). Conclusions: Our findings underscore the potential value of this novel six-miRNA signature both as a prognostic and diagnostic biomarker in NSCLC. Its correlation with immune microenvironment characteristics supports its relevance in guiding personalized therapeutic strategies. This signature warrants further clinical validation and may serve as a valuable tool for patient stratification and outcome prediction for patients treated with platinum-based chemotherapy.
SN - 2072-6694
ER -