Integrated microRNA, gene expression and transcription factors signature in papillary thyroid cancer with lymph node metastasis
- Published
- Accepted
- Subject Areas
- Molecular Biology, Oncology
- Keywords
- Papillary thyroid carcinoma, lymph node, microRNA, gene expression
- Copyright
- © 2015 Ab Mutalib et al.
- Licence
- This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ PrePrints) and either DOI or URL of the article must be cited.
- Cite this article
- 2015. Integrated microRNA, gene expression and transcription factors signature in papillary thyroid cancer with lymph node metastasis. PeerJ PrePrints 3:e1535v1 https://doi.org/10.7287/peerj.preprints.1535v1
Abstract
Background: Papillary thyroid carcinoma (PTC) is the commonest thyroid malignancy originating from the follicle cells in the thyroid. Despite a good overall prognosis, certain high-risk cases as in those with lymph node metastasis (LNM) have progressive disease and poorer prognosis. MicroRNAs are a class of non-protein-coding, 19-24 nucleotides single-stranded RNAs which regulate gene expression and these molecules have been shown to play a role in LNM. The integrated analysis of miRNAs and gene expression profiles together with transcription factors (TFs) has been shown to improve the identification of functional miRNA-target gene-TF relationships, providing a more complete view of molecular events underlying metastasis process. Objectives: We reanalyzed The Cancer Genome Atlas (TCGA) datasets on PTC to identify differentially expressed miRNAs/genes in PTC patients with LNM-positive (LNM-P) versus lymph node negative (LNN) PTC patients and to investigate the miRNA-gene-TF regulatory circuit that regulate LNM in PTC. Results: PTC patients with LNM (PTC LNM-P) has significantly shorter disease-free survival rate compared to PTC patients without LNM (PTC LNN) (Log-rank Mantel Cox test, p = 0.0049). We identified 181 significantly differentially expressed miRNAs in PTC LNM-P versus PTC LNN; 110 were upregulated and 71 were downregulated. The five topmost deregulated miRNAs were hsa-miR-146b, hsa-miR-375, hsa-miR-31, hsa-miR-7-2 and hsa-miR-204. In addition, 395 miRNAs were differentially expressed between PTC LNM-P and normal thyroid while 400 miRNAs were differentially expressed between PTC LNN and normal thyroid. We found 4 significant enrichment pathways potentially involved in metastasis to the lymph nodes namely oxidative phosphorylation (OxPhos), cell adhesion molecules (CAMs), leukocyte transendothelial migration and cytokine-cytokine receptor interaction. OxPhos was the most significantly perturbed pathway (p = 4.70E-06) involving downregulation of 90 OxPhos-related genes. Significant interaction of hsa-miR-301b with HLF, HIF and REL/NFkB transcription factors were identified exclusively in PTC LNM-P versus PTC LNN. Conclusion: We found evidence of five miRNAs differentially expressed in PTC LNM-P. Alteration in OxPhos pathway could be the central event in metastasis to the lymph node in PTC. We postulate that hsa-miR-301b might be involved in regulating LNM in PTC via interactions with HLF, HIF and REL/NFkB. To the best of our knowledge, the roles of these TFs have been studied in PTC but the precise role of this miRNA with these TFs in LNM in PTC has not been investigated.
Author Comment
This is a submission to PeerJ for review.
Supplemental Information
TCGA sample IDs of 477 papillary thyroid cancer patients with microRNA and gene expression data
181 significantly deregulated miRNAs with respective log2 fold change and p value in PTC LNM-P versus PTC LNN
78 significantly deregulated miRNAs with respective log2 fold change and p value in PTCs (LNM-P and LNN) versus normal thyroid
407 significantly deregulated genes with respective log2 fold change and p value in PTC LNM-P versus PTC LNN
Heat Map of the 395 Differentially Expressed miRNAs in PTC LNM-P versus normal thyroid. (Student's T-test with BH corrected p value ≤0.05)
Heat Map of the 400 Differentially Expressed miRNAs in PTC LNN versus normal thyroid. (Student's T-test with BH corrected p value ≤0.05)
Top 20 mixed regulatory circuits, involving miRNAs, genes and TFs
There are two types of mixed regulatory circuits; a TF regulating both a given miRNA and its target gene and a miRNA that regulates both a given TF and its regulated gene. (A) PTC LNM-P compared to PTC LNN. (B) PTC LNM-P compared to normal thyroid. (C) PTC LNN compared to normal thyroid.
