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Published on: March 30, 2019
Typical Lung Carcinoids with Metastasis: Potential Role of MicroRNAs in the Regulation of Adaptive Immunity
Ana L Seneda1,2, Rainer M Lopez Lapa3,4, Tainara F Felix1,2
1Faculty of Medicine, Department of Surgery and Orthopedics, São Paulo State University (UNESP), Botucatu, Brazil.
Background/Aims:
Lung carcinoids are uncommon neuroendocrine tumours. Molecular features of lung carcinoids have been poorly defined. microRNAs (miRNAs) are potent gene expression regulators with important roles in cancer development and progression. However, little is known on the role of miRNAs in the pathogenesis of lung carcinoids. Our goals were to identify commonly deregulated miRNAs in a rare case of lung carcinoid of typical histology with metastasis, as well as map miRNA target genes in pathways potentially associated with disease development and progression.
Methods:
miRNA expression profiles were assessed using the TaqMan Low Density Arrays, which is a platform including 384 miRNAs. miRNA profiles were generated in the tumor and its corresponding lymph node metastasis, compared to reference normal lung tissues. Furthermore, miRNA expression was validated in a separate, publicly available external dataset (n=19 typical lung carcinoids; 2/19 were metastatic tumors, compared to six normal lung tissues, GSE77380). Following this analysis, computational tools were applied for data interpretation. miRTarBase was used to determine miRNA-target genes, followed by ToppGene Suite analysis to identify pathways and biological functions. In addition, the expression of genes targeted by miRNAs was validated in a second, separate external dataset (n=13 tumour samples, GSE35679). GEO2R data analysis tool was used in both validation analyses (miRNAs and genes).
Results:
We identified 15 commonly significantly downregulated miRNAs (fold change, FC≥2 and p<0.05) in the tumour and its paired metastasis, with further decreasing levels in the metastatic lesion. Downregulation of miR-126-3p and miR-146b-5p was validated in the external dataset GSE77380. In addition, SOX2 and TCF4 genes, targeted by miR-126-3p, were consistently overexpressed in a subset of six typical lung carcinoids from the external dataset GSE35679. Pathways analysis showed that miRNAs miR-126-3p and miR-146b-5p target genes with a role in the regulation of adaptive immune response.
Conclusion:
Our results contribute to the identification of miRNA expression changes in a typical lung carcinoid and its corresponding lymph node metastasis. Down-regulated levels of miR-126-3p and miR-146b-5p and target gene over-expression could play a role in the progression of this case of primary typical lung carcinoid to regional metastasis. Identified miRNAs and target genes are potential candidates for validation in a larger number of cases.
Insights
This study identified 15 downregulated microRNAs (miRNAs) in lung carcinoid tumors and metastases. Key miRNAs, miR-126-3p and miR-146b-5p, and their target genes may drive lung carcinoid progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Lung carcinoids are rare neuroendocrine tumors with poorly understood molecular characteristics.
- MicroRNAs (miRNAs) are critical gene regulators implicated in cancer development, but their role in lung carcinoids remains largely unexplored.
- This study aimed to identify deregulated miRNAs and their target genes in typical lung carcinoid with metastasis to understand disease progression.
Observation:
- A total of 15 significantly downregulated miRNAs were identified in lung carcinoid tumors and lymph node metastases.
- The expression levels of miR-126-3p and miR-146b-5p were validated as decreased in an external dataset.
- Overexpression of SOX2 and TCF4 genes, targeted by miR-126-3p, was observed in a subset of lung carcinoid samples.
Findings:
- Downregulation of miR-126-3p and miR-146b-5p was consistently observed in lung carcinoid tumors and metastases.
- Target gene analysis revealed that these miRNAs regulate pathways involved in adaptive immune response.
- SOX2 and TCF4 gene overexpression, potentially driven by miR-126-3p downregulation, was noted in lung carcinoid samples.
Implications:
- The identified downregulated miRNAs (miR-126-3p, miR-146b-5p) and their overexpressed target genes (SOX2, TCF4) are potential biomarkers for lung carcinoid progression.
- These molecular changes may play a crucial role in the transition of typical lung carcinoids to regional metastasis.
- Further validation in larger cohorts is warranted to confirm the clinical utility of these miRNA and gene expression alterations.
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