Abstract
Simple SummaryInteraction between blood platelets and cancer cells play an important role in various steps of cancer development and progression. These interactions lead to changes in the platelets’ RNA content, resulting in tumor-mediated “education” of platelets. Tumor-educated platelets (TEPs) can be used as a non-invasive biomarker source for cancer detection and progression monitoring. Our lab has previously identified that spliced mRNA TEP signatures provide specific information on the presence, location, and molecular features of cancers. Next to mRNA, other RNA types are present in platelets, and their repertoire can potentially be subjected to cancer-mediated alterations. Despite the evidence that circRNA could be a promising cancer biomarker, they have not yet been analyzed in blood platelets of cancer patients. In this proof-of-concept study, we aim to evaluate whether platelets’ circRNA signature could be used as a biomarker for cancer detection and progression.Tumor-educated Platelets (TEPs) have emerged as rich biosources of cancer-related RNA profiles in liquid biopsies applicable for cancer detection. Although human blood platelets have been found to be enriched in circular RNA (circRNA), no studies have investigated the potential of circRNA as platelet-derived biomarkers for cancer. In this proof-of-concept study, we examine whether the circRNA signature of blood platelets can be used as a liquid biopsy biomarker for the detection of non-small cell lung cancer (NSCLC). We analyzed the total RNA, extracted from the platelet samples collected from NSCLC patients and asymptomatic individuals, using RNA sequencing (RNA-Seq). Identification and quantification of known and novel circRNAs were performed using the accurate CircRNA finder suite (ACFS), followed by the differential transcript expression analysis using a modified version of our thromboSeq software. Out of 4732 detected circRNAs, we identified 411 circRNAs that are significantly (p-value < 0.05) differentially expressed between asymptomatic individuals and NSCLC patients. Using the false discovery rate (FDR) of 0.05 as cutoff, we selected the nuclear receptor-interacting protein 1 (NRIP1) circRNA (circNRIP1) as a potential biomarker candidate for further validation by reverse transcription–quantitative PCR (RT-qPCR). This analysis was performed on an independent cohort of platelet samples. The RT-qPCR results confirmed the RNA-Seq data analysis, with significant downregulation of circNRIP1 in platelets derived from NSCLC patients. Our findings suggest that circRNAs found in blood platelets may hold diagnostic biomarkers potential for the detection of NSCLC using liquid biopsies.
Highlights
Circular RNAs are a type of RNAs characterized by a covalently closed loop structure
To investigate whether the circular RNA (circRNA) profile in platelets may hold the potential as noninvasive biomarkers for non-small cell lung cancer (NSCLC) detection, we performed RNA-sequencing of 12 platelet samples derived from both NSCLC patients (n = 6) and asymptomatic individuals (n = 6) (Table 1, Figure 1a, Supplementary Figure S1)
CircRNA could represent a promising biomarker for liquid biopsy, the potential to detect NSCLC based on their profile in platelets was not investigated yet
Summary
Circular RNAs (circRNAs) are a type of RNAs characterized by a covalently closed loop structure. They are generated by an alternative splicing mechanism called back splicing in which a downstream 5 splice site binds an upstream 3 splicing site of a pre-mRNA molecule [1]. CircRNAs can be found in almost all human cell types analyzed far, and occasionally, they are more abundant than their linear counterparts [5,7]. Their high stability, abundance, and spatiotemporal specific expression [8] suggest that circRNAs may have a better analytical validity over canonical linear RNA as the biomarker
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