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The Analysis of Platelet-Derived circRNA Repertoire as Potential Diagnostic Biomarker for Non-Small Cell Lung Cancer.

ABSTRACT: 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.

SUBMITTER: D'Ambrosi S

PROVIDER: S-EPMC8468408 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTo date, the role of programmed death ligand-1 (PD-L1) messenger RNA (mRNA) derived from tumor-educated platelets (TEPs) has not been well investigated in patients with advanced non-small cell lung cancer (NSCLC). A few reports have examined whether mRNA in TEPs can predict the clinical responses of patients with advanced NSCLC following immunotherapy. This study aimed to identify novel biomarkers to improve the clinical benefits and outcomes of NSCLC patients.MethodsAdvanced NSCLC patients receiving a combination of immunotherapy and chemotherapy, or immunotherapy alone as a first- or second-line treatment at the Fudan University Shanghai Cancer Center were enrolled in this study. All the patients had wild-type epidermal growth factor receptor/anaplastic lymphoma kinase. The patients were enrolled in clinical trials for immune checkpoint inhibitors (ICIs), including nivolumab, pembrolizumab, atezolizumab, durvalumab, tremelimumab, and camrelizumab. Tumoral PD-L1 expression was tested by immunohistochemistry (PD-L1 22C3 pharmDx kit, Agilent, Santa Clara, CA, USA) in archived tissue samples, when available, to calculate the tumor proportion scores (TPSs). RNA and exosomal RNA of blood were isolated before immunotherapy using the Yunying RNA extraction kit (Yunying Medicine, Shanghai, China). The concentration and quality of the RNA was determined using a Qubit fluorometer (Life Technologies, Carlsbad, CA, USA). Finally, we analyzed the predictive value of TEP-derived PD-L1 mRNA expression and association with the level of the tumoral PD-L1 expression.ResultsIn total, 72 patients were enrolled in this study. Most of the patients were male (n=54, 75.0%), had adenocarcinoma (n=49, 68.1%). We found there was no significant correlation between the TEP-derived mRNA of PD-L1 and tumoral PD-L1 expression based on the results of the Pearson Correlation test (r=-0.19, P=0.233). Based on the median of PD-L1 mRNA, 72 patients were divided into a high PD-L1 group and a low PD-L1 group. We found that 19 patients (44.4%) responded to immunotherapy [partial response or progression-free survival (PFS) >6 months] in the high PD-L1 group, but only five patients (13.9%) responded to immunotherapy in the low PD-L1 group (P<0.01). The median PFS of the low PD-L1 group was lower than that of the high PD-L1 group (2.8 vs. 8.3 months, P<0.001). For the patients who were treated with immunotherapy alone (n=64), a similar PFS advantage was observed in the high PD-L1 group (2.8 vs. 8.0 months, P=0.002).ConclusionsThis article presented the first data on TEP-derived PD-L1 mRNA in advanced NSCLC patients following immunotherapy and showed the potential advantage of using it as the surrogate biomarker for predicting the PFS and overall survival of patients following immunotherapy.

Project description:Current evidence suggests that DEP domain containing 1 (DEPDC1) has an important effect on non-small-cell lung cancer (NSCLC). However, the diagnostic value and the regulatory function within NSCLC are largely unclear. This work utilized publicly available databases and in vitro experiments for exploring, DEPDC1 expression, clinical features, diagnostic significance and latent molecular mechanism within NSCLC. According to our results, DEPDC1 was remarkably upregulated in the tissues of NSCLC patients compared with non-carcinoma tissues, linked with gender, stage, T classification and N classification based on TCGA data and associated with smoking status and stage according to GEO datasets. Meanwhile, the summary receiver operating characteristic (sROC) curve analysis result showed that DEPDC1 had a high diagnostic value in NSCLC (AUC = 0.96, 95% CI: 0.94-0.98; diagnostic odds ratio = 99.08, 95%CI: 31.91-307.65; sensitivity = 0.89, 95%CI: 0.81-0.94; specificity = 0.92, 95%CI: 0.86-0.96; positive predictive value = 0.94, 95%CI: 0.89-0.98; negative predictive value = 0.78, 95%CI: 0.67-0.90; positive likelihood ratio = 11.77, 95%CI: 6.11-22.68; and negative likelihood ratio = 0.12, 95%CI: 0.06-0.22). Subsequently, quantitative real-time PCR (qRT-PCR) and western blotting indicated that DEPDC1 was high expressed in NSCLC cells. According to the in vitro MTS and apoptotic assays, downregulated DEPDC1 expression targeting P53 signaling pathway inhibited the proliferation of NSCLC cells while promoting apoptosis of NSCLC cells. Moreover, DEPDC1 was significantly correlated with immune cell infiltrating levels in NSCLC based on TCGA data, which were primarily associated with T cells CD4 memory activated, macrophages M1, B cells memory, mast cells resting, T cells regulatory, monocytes, and T cells CD4 memory resting. Compared with the group with high expression of DEPDC1, the group with low expression level had higher scores for immune checkpoint inhibitors (ICIs) treatment. GSEA confirmed that DEPDC1 was involved in gene expression and tumor-related signaling pathways. Finally, DEPDC1 and its associated immune-related genes were shown to be enriched in 'receptor ligand activity', 'external side of plasma membrane', 'regulation of innate immune response', and 'Epstein-Barr virus infection' pathways. The present study demonstrates that DEPDC1 may contribute to NSCLC tumorigenesis and can be applied as the biomarker for diagnosis and immunology.

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The Analysis of Platelet-Derived circRNA Repertoire as Potential Diagnostic Biomarker for Non-Small Cell Lung Cancer.

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