MicroRNA Profiling of Red Blood Cells for Lung Cancer Diagnosis

SIMPLE SUMMARY: Despite extensive efforts to identify cell-free circulating biomarkers for lung cancer, none have yet achieved clinical adoption. Recent evidence suggests that blood cell-derived molecules play significant roles in tumorigenesis and may serve as potential diagnostic biomarkers. In this study, we perform microRNA (miRNA) profiling on three primary blood cell types: red blood cells (RBCs), peripheral blood mononuclear cells, and neutrophils, comparing samples from lung cancer patients to healthy controls. We identify distinct miRNA signatures for each cell type and observe significant differences between patient and control cohorts. We show for the first time that RBC-miRNAs have potential as novel biomarkers for lung cancer. By constructing diagnostic panels based on cell-specific miRNAs, we demonstrate that integrating miRNAs from multiple cell sources offers superior diagnostic accuracy than relying on a single cell type. ABSTRACT: Background: Despite extensive endeavors to establish cell-free circulating biomarkers for lung cancer diagnosis, clinical adoption remains elusive. Noteworthy, emergent evidence suggests the pivotal roles of red blood cells (RBCs) and their derivatives in tumorigenesis, illuminating potential avenues for diagnostic advancements using blood cell-derived microRNAs (miRNAs). Methods: We executed microarray analyses on three principal blood cell types—RBCs, peripheral blood mononuclear cells (PBMCs), and neutrophils—encompassing 26 lung cancer patients and 26 healthy controls. Validation was performed using droplet digital PCR within an additional cohort comprising 42 lung cancer and 39 control cases. Results: Our investigation unearthed distinct miRNA profiles associated with lung cancer across all examined blood cell types. Intriguingly, RBC-miRNAs emerged as potential novel biomarkers for lung cancer, an observation yet to be documented. Importantly, integrating miRNAs from disparate blood cell types yielded a superior diagnostic accuracy for lung cancer over individual cell-type miRNAs. Subsequently, we formulated three diagnostic panels, adeptly discerning non-small cell lung cancer, adenocarcinoma, and squamous cell carcinoma, maintaining consistency across various disease stages. Conclusion: RBC-derived molecules introduce novel cancer biomarkers, and exploiting miRNA profiles across varied blood cell types unveils a promising frontier for lung cancer’s early detection and histological classification.