Background/Aims: Micro-RNA (miR)-146b-5p is overexpressed in papillary thyroid carcinoma (PTC) and associated with extrathyroidal invasion and advanced tumor stage. In the present study, we showed that miR-146b-5p is upregulated in PTC with lymph node metastasis. Methods: A computational search and luciferase assay identified zinc RING finger 3 (ZNRF3), a negative regulator of Wnt/β-catenin signaling, as a direct target of miR-146b-5p in PTC. Results: MiR-146b-5p promoted migration and invasiveness and induced epithelial-mesenchymal transition (EMT) of PTC cells, whereas ZNRF3 overexpression reversed this effect. MiR-146b-5p increased the cell surface levels of the Wnt receptors Frizzled-6 and LRP6 and enhanced Wnt/β-catenin signaling by downregulating ZNRF3, whereas an inhibitor of Wnt/β-catenin suppressed the effect of miR-146b-5p on migration, invasiveness and EMT of PTC cells. Conclusion: These results indicate that miR-146b-5p induces EMT and may promote PTC metastasis through the regulation of Wnt/β-catenin signaling, and suggest novel potential therapeutic targets for the treatment of PTC.

microRNAs (miRNAs) are involved in the pathogenesis of diverse human cancers through its target genes, including papillary thyroid cancer (PTC). However, there are few studies regarding associations between clinicopathological features of PTC with the expression of specific miRNAs and its potential target genes. In the present study, analysis of miRNA was integrated with mRNA expression profiles in aggressive PTC. miRNA and gene expression arrays were used to identify a subset of differentially expressed miRNAs and mRNAs between aggressive and non-aggressive PTCs. These miRNAs and mRNAs were further validated by qPCR in a cohort of 20 PTCs with extrathyroidal invasion and/or distant metastases, and 20 PTCs with no extrathyroidal invasion. The target of these miRNAs was determined by luciferase reporter and bioinformatic analysis. The miRNA arrays identified 14 upregulated miRNAs and 10 downregulated miRNAs in aggressive compared with non-aggressive PTCs. Significant miRNA deregulation was confirmed in the validation cohort, with upregulation of miR-146b-5p and miR-221/222 and downregulation of miR-16 and miR-613 in aggressive PTCs. The gene arrays identified 2000 differentially expressed genes, in which TIMP3, ZNFR3, FN1 and ITGA2 were observed to be target genes inversely correlated with miR-221/222, miR-146b-5p, miR-613 and miR-16, respectively. The results of the present study indicated the potential importance of miR-221/222, miR-146b-5p, miR-16 and miR-613 in determining the aggressive properties of PTC by targeting TIMP3, ZNFR3, FN1 and ITGA2, respectively. Additional studies should be conducted to confirm the results.

Cytochrome P450s enzymes catalyze the metabolism of arachidonic acid to epoxyeicosatrienoic acids (EETs), dihydroxyeicosatetraenoic acid and hydroxyeicosatetraeonic acid (HETEs). 20-HETE is a vasoconstrictor that depolarizes vascular smooth muscle cells by blocking K+ channels. EETs serve as endothelial derived hyperpolarizing factors. Inhibition of the formation of 20-HETE impairs the myogenic response and autoregulation of renal and cerebral blood flow. Changes in the formation of EETs and 20-HETE have been reported in hypertension and drugs that target these pathways alter blood pressure in animal models. Sequence variants in CYP4A11 and CYP4F2 that produce 20-HETE, UDP-glucuronosyl transferase involved in the biotransformation of 20-HETE and soluble epoxide hydrolase that inactivates EETs are associated with hypertension in human studies. 20-HETE contributes to the regulation of vascular hypertrophy, restenosis, angiogenesis and inflammation. It also promotes endothelial dysfunction and contributes to cerebral vasospasm and ischemia-reperfusion injury in the brain, kidney and heart. This review will focus on the role of 20-HETE in vascular dysfunction, inflammation, ischemic and hemorrhagic stroke and cardiac and renal ischemia reperfusion injury.

Our results indicate that miR-155 functions as an oncogene in PTC. By targeting APC, miR-155 efficiently regulates the Wnt/β-catenin signaling. And miR-155 may be a potential therapeutic or diagnostic/prognostic target for treating PTC.