A Prognostic Role for Circulating microRNAs Involved in Macrophage Polarization in Advanced Non-Small Cell Lung Cancer.
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ABSTRACT:
SUBMITTER: Monastirioti A
PROVIDER: S-EPMC8391493 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Non-small cell lung cancer (NSCLC) is the primary cause of cancer-related death worldwide, with a low 5-year survival rate even in fully resected early-stage disease. Novel biomarkers to identify patients at higher risk of relapse are needed. We studied the prognostic value of 84 circulating microRNAs (miRNAs) in 182 patients with resected early-stage NSCLC (99 adenocarcinoma (ADC), 83 squamous cell carcinoma (SCC)) from whom peripheral blood samples were collected pre-surgery. miRNA expression was analyzed in relation to disease-free survival (DFS) and overall survival (OS). In univariable analyses, five miRNAs (miR-26a-5p, miR-126-3p, miR-130b-3p, miR-205-5p, and miR-21-5p) were significantly associated with DFS in SCC, and four (miR-130b-3p, miR-26a-5p, miR-126-3p, and miR-205-5p) remained significantly associated with OS. In ADC, miR-222-3p, miR-22-3p, and mir-93-5p were significantly associated with DFS, miR-22-3p remaining significant for OS. Given the high-dimensionality of the dataset, multivariable models were obtained using a regularized Cox regression including all miRNAs and clinical covariates. After adjustment for disease stage, only miR-126-3p showed an independent prognostic role, with higher values associated with longer DFS in SCC patients. With regard to ADC and OS, no miRNA remained significant in multivariable analysis. Further investigation into the role of miR-126 as a prognostic marker in early-stage NSCLC is warranted.
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Project description:Macrophages are among the most common cells in the colorectal cancer microenvironment, but their prognostic significance is incompletely understood. Using multiplexed immunofluorescence for CD68, CD86, IRF5, MAF, MRC1 (CD206), and KRT (cytokeratins) combined with digital image analysis and machine learning, we assessed the polarization spectrum of tumor-associated macrophages in 931 colorectal carcinomas. We then applied Cox proportional hazards regression to assess prognostic survival associations of intraepithelial and stromal densities of M1-like and M2-like macrophages while controlling for potential confounders, including stage and microsatellite instability status. We found that high tumor stromal density of M2-like macrophages was associated with worse cancer-specific survival, whereas tumor stromal density of M1-like macrophages was not significantly associated with better cancer-specific survival. High M1:M2 density ratio in tumor stroma was associated with better cancer-specific survival. Overall macrophage densities in tumor intraepithelial or stromal regions were not prognostic. These findings suggested that macrophage polarization state, rather than their overall density, was associated with cancer-specific survival, with M1- and M2-like macrophage phenotypes exhibiting distinct prognostic roles. These results highlight the utility of a multimarker strategy to assess the macrophage polarization at single-cell resolution within the tumor microenvironment.
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Project description:Background:MicroRNAs (miRNAs) have been found to play an important role in the development and outcomes for multiple human cancers. Their role as a prognostic biomarker in non-small-cell lung cancer (NSCLC) remains unclear. This meta-analysis aims to clarify the role of various miRNAs in the survival of NSCLC patients. Materials and Methods:All studies were identified through medical database search engines. A meta-analysis was conducted to assess the correlation between miRNAs expressions and overall survival among those NSCLC studies. Relevant data were extracted from each eligible study regarding baseline characteristics and key statistics such as hazard ratio (HR), 95% confidence interval (CI), and P value, which were utilized to calculate a pooled effect size. Result:Thirty-two studies were included in the meta-analysis. Using a random effect model, the combined HR and 95% CI for overall survival (OS) was calculated as 1.59 (1.39-1.82), predicting a poor overall survival. Five miRNAs (miR-21, miR-155, miR-let-7, miR-148a, and miR-148b) were found to be of significance for predicting OS in at least two studies, hence, selected for subgroup analysis. Subgroup analysis disclosed that elevated levels of miR-21 and miR-155 in both cancer tissue and blood samples were associated with worse OS. Compared to American studies (I-squared: <0.001% and P value: 0.94), Asian and European studies exhibited greater heterogeneity in miRNA expression and relationship to OS (I-squared, P values were approximately 78.85%, <0.001 and 61.28%, 0.006, respectively). These subgroup analyses also highlighted that elevated expression of miR-21 and miR-155 and low levels of expression of miR-148a, miR-148b, and miR-let-7 were associated with poor prognosis in NSCLC. Conclusion:miR-21, miR-155, miR-148a, miR-148b, and miR-let-7 are consistently up- or downregulated in NSCLC and are associated with poor OS. These miRNAs show potential as useful prognostic biomarkers in the diagnosis, treatment, and follow-up of NSCLC.
| S-EPMC6260404 | biostudies-literature
Project description:Cell-free DNA (cfDNA) and circulating tumor cells (CTCs) are promising prognostic and predictive biomarkers in non-small cell lung cancer (NSCLC). In this study, we examined the prognostic role of cfDNA and CTCs, in separate and joint analyses, in NSCLC patients receiving first line chemotherapy. Seventy-three patients with advanced NSCLC were enrolled in this study. CfDNA and CTC were analyzed at baseline and after two cycles of chemotherapy. Plasma cfDNA quantification was performed by quantitative PCR (qPCR) whereas CTCs were isolated by the ScreenCell Cyto (ScreenCell, Paris, France) device and enumerated according to malignant features. Patients with baseline cfDNA higher than the median value (96.3 hTERT copy number) had a significantly worse overall survival (OS) and double the risk of death (hazard ratio (HR): 2.14; 95% confidence limits (CL) = 1.24-3.68; p-value = 0.006). Conversely, an inverse relationship between CTC median baseline number (6 CTC/3 mL of blood) and OS was observed. In addition, we found that in patients reporting stable disease (SD), the baseline cfDNA and CTCs were able to discriminate patients at high risk of poor survival. cfDNA demonstrated a more reliable biomarker than CTCs in the overall population. In the subgroup of SD patients, both biomarkers identified patients at high risk of poor prognosis who might deserve additional/alternative therapeutic interventions.
| S-EPMC5454947 | biostudies-other
Project description:BackgroundHuman endogenous retrovirus-H long terminal repeat-associating protein 2 (HHLA2) is a member of B7 family, which is upregulated in multiple tumors. However, its exact functions in non-small cell lung cancer (NSCLC) have not been fully understood. This study aimed to investigate the biological roles of HHLA2 in human NSCLC and the relevant mechanisms. In addition, the effects of tumor cell-derived HHLA2 on tumor-associated macrophage (TAM) polarization were explored.MethodsNSCLC cell growth, migration, and invasion were assessed by colony formation and modified Boyden chamber assays. Cell cycle and the CD163+ TAMs were examined by flow cytometry. A co-culture model of THP-1 macrophages and NSCLC cells was conducted to investigate the impacts of tumor cell-derived HHLA2 on THP-1 macrophage polarization. Moreover, a xenograft nude mouse model was established to explore the effects of HHLA2 on tumorigenesis in vivo.ResultsHHLA2 was upregulated in A549 and H1299 cells compared with the normal lung epithelial BEAS-2B cells. HHLA2 deficiency inhibited NSCLC cell proliferation, migration, invasion, and induced G0/G1 phase arrest partially via inhibiting EGFR/MAPK/ERK signaling pathway. Furthermore, HHLA2 knockdown inhibited M2 polarization of TAMs via downregulating IL-10. In addition, knockdown of HHLA2 inhibited tumor growth in vivo.ConclusionHHLA2 downregulation inhibited NSCLC growth and TAM M2 polarization. HHLA2 may serve as a therapeutic target and promising prognostic biomarker in NSCLC.
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Project description:BackgroundAcute rejection (AR) and development of chronic rejection, bronchiolitis obliterans syndrome (BOS) remain major limiting factors for lung transplantation (LTx). This retrospective study is to identify differentially expressed circulating microRNAs (miRNAs) that associate with development of AR and BOS in pediatric lung transplant recipients (LTxR).MethodsWe determined the circulating levels of 7 selected candidate miRNAs in 14 LTxR with AR, 7 with BOS, and compared them against 13 stable pediatric LTxR at 1, 6, and 12 months after LTx. In addition, 6 AR, 7 BOS, and 8 stable pediatric LTxR, 16 AR, 17 BOS, and 16 stable adult LTxR were included for validation.ResultsMiR-10a, -195, -133b were significantly lower in AR and miR-144, -142-5p, -155 were higher in AR compared to stable (P < 0.05). In addition, circulating levels of miR-134, -10a, -195, -133b were significantly lower and miR-144, -142-5p, -155 were higher (P < 0.05) with development of BOS. The receiver-operating characteristic demonstrated that miR-142-5p, miR-155, and miR-195 strongly discriminated patients with AR from stable LTxR (P < 0.001 for all comparisons): miR-142-5p (area under the curve [AUC], 0.854), miR-155 (AUC, 0.876), and miR-195 (AUC, 0.872). Further, miR-10a, miR-142-5p, miR-144, and miR-155 strongly discriminated BOS from stable LTxR (P < 0.001 for all comparisons).ConclusionsWe demonstrated that differential expression of circulating miRNAs occurs in LTxR with AR and BOS, suggesting that they can provide not only important clues to pathogenesis but also may serve as potential noninvasive biomarkers for AR and BOS after pediatric LTx.
| S-EPMC5462875 | biostudies-literature
Project description:Introduction: Accumulating evidence showed that a large number of microRNAs (miRNAs) are abnormally expressed in lung cancer tissues and play critical roles in cancer development and progression. The aim of this study is to identify the differentially expressed miRNAs (DEMs) between non-small cell lung cancer (NSCLC) and normal lung tissues, and evaluate the prognostic value and potential target gene functional enrichment of the DEMs. Materials and Methods: We first downloaded the high-throughput miRNA data from The Cancer Genome Atlas Project (TCGA) database, and subsequently analyzed the data using bioinformatics analysis including limma package in R, Kaplan-Meier curve and Log-rank method, and several online analysis tools. Results: A total of 125 DEMs and 138 DEMs were respectively identified in lung adenocarcinoma (LUAD) tissues and lung squamous cell carcinoma (LUSC) tissues compared with their matched normal tissues. Moreover, we found that the prognostic function of the eight miRNAs (miR-375, miR-148a, miR-29b-1 and miR-584 for LUAD; miR-4746, miR-326, miR-93 and miR-671 for LUSC). Furthermore, the two four-miRNA signatures were constructed and found to be an independent prognostic factor for LUAD and LUSC patients, respectively. Additionally, our results indicated that the target genes of eight miRNAs may be involved in various pathways related to NSCLC, including PI3K-Akt, TGF-beta, FoxO, Ras, GPI-anchor biosynthesis and metabolic, Rap1, HIF-1 and proteasome. Conclusion: Overall, eight miRNAs were closely correlated with survival of NSCLC patients, and the constructed two four-miRNA signatures could be respectively used as prognostic markers in LUAD and LUSC patients.
| S-EPMC6843868 | biostudies-literature
Project description:BackgroundCirculating tumor cell (CTC) counts at baseline and follow-up are an independent prognostic factor in patients receiving standard chemotherapy for non-small cell lung cancer (NSCLC). This study further explored the role of CTCs in EGFR-mutated and ALK-rearranged NSCLC patients administered targeted therapies as first-line treatment.MethodsCTCs were enumerated with a novel high-efficiency detection method from the blood of 43 patients with EGFR-mutated or ALK-rearranged NSCLC at baseline and at disease-progression. Patients were stratified into favorable and unfavorable groups with baseline CTC counts of < 8 or ≥ 8 CTCs/3.2 mL, respectively.ResultsA total of 76.7% of the patients were positive for ≥ 2 CTCs /3.2 ml blood at baseline. The median progression-free survival (PFS) and overall survival (OS) rates of the favorable compared to the unfavorable group were longer (11.6 vs. 8.5 months, P = 0.004 for PFS; 21.00 vs. 17.7 months, P = 0.013 for OS). Multivariate analysis demonstrated that baseline CTC count was a strong predictor of PFS (hazard ratio 2.835; 95% confidence interval 1.240-6.483; P = 0.014) and OS (hazard ratio 3.317; 95% confidence interval 1.360-8.092; P = 0.008).ConclusionBaseline CTC count could be a predictive biomarker for EGFR-mutated and ALK-rearranged NSCLCs, which allows for better guidance and monitoring of patients over the course of molecular targeted therapies.
| S-EPMC5928386 | biostudies-literature