Integrated microRNA, gene expression and transcription factors signature in papillary thyroid cancer with lymph node metastasis

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) have a 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 four 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.

Peer Review #2 of "MicroRNA-705 regulates the differentiation of mouse mandible bone marrow mesenchymal stem cells (v0.1)"

“…Manuscript to be reviewed translational inhibition (Ab Mutalib et al 2016;Bartel 2009;Yang et al 2017).…”

“…Manuscript to be reviewed uncover the regulatory mechanism of mandibular MSCs. miRNAs function by base pairing to complementary sites in the 3' untranslated region (3'UTR) of mRNAs (Ab Mutalib et al 2016;Bartel 2009). The connections between miRNAs and the cell lineage commitment of MSCs have been demonstrated by several studies using BMMSCs from femurs (Chen et al 2016).…”

Identification of potential prognostic microRNA biomarkers for predicting survival in patients with hepatocellular carcinoma

“…For instance, miRNA expression-based prognostic signatures, which were identified by Cox proportional regression models in cancer prognosis prediction using TCGA datasets, have been developed in multiple cancers, such as pancreatic cancer, 26 , 27 stomach adenocarcinoma, 28 head and neck squamous cell carcinoma, 29 , 30 gliomas, 31 glioblastoma, 32 – 34 cervical cancer, 35 bladder cancer, 36 breast cancer, 37 , 38 colon cancer, 39 lung cancer, 40 , 41 and HCC. 42 – 44 In addition, diagnostic 45 – 47 and metastasis 48 related miRNA signature biomarkers have been investigated in multiple cancers using TCGA datasets. Updates in the TCGA HCC dataset and the miRNA expression-based prognostic signatures require comprehensive survival analysis to validate; therefore, further investigations of miRNA expression prognostic signatures with a reliable method and comprehensive evaluation is necessary.…”

Integrated Characterization of MicroRNA and mRNA Transcriptome in Papillary Thyroid Carcinoma

“…There are two miRNAs that are involved in both comparison groups, namely, hsa-miR-7-5p and hsa-miR-181b-5p, hence suggesting that both miRNAs are involved in the pathogenesis of PTC in general and are not specific to LNM. Various studies have reported that hsa-miR-7-5p has a low expression level in PTC samples ( 13 , 31 , 50 ). Hsa-miR-7 plays a role in regulating cell growth, migration, and invasion by targeting PAK1 in thyroid cancer ( 51 ).…”