Next-Generation Sequencing Identifies a Highly Accurate miRNA Panel That Distinguishes Well-Differentiated Thyroid Cancer from Benign Thyroid Nodules

Mazeh, Haggi; Deutch, Tova; Karas, Adi; Bogardus, Kimberly A.; Mizrahi, Ido; Gur‐Wahnon, Devorah; Ben‐Dov, Iddo Z.

doi:10.1158/1055-9965.epi-18-0055

Cited by 28 publications

(27 citation statements)

References 21 publications

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“…Compared with lncRNA, miRNAs have been much more thoroughly studied in the thyroid, and some of them have actually entered clinical practice as parts of diagnostic panels to distinguish benign from malignant thyroid nodules in cases of indeterminate fine-needle aspiration cytology results [ 50 , 51 ]. In the present study, 70 miRNAs were found to respond to iodide excess ( Tables S7 and S8, Supplementary Materials ).…”

Section: Discussionmentioning

confidence: 99%

The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System

Chartoumpekis

Ziros

Georgakopoulos-Soares

et al. 2020

Antioxidants

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Background: Thyroid follicular cells have physiologically high levels of reactive oxygen species because oxidation of iodide is essential for the iodination of thyroglobulin (Tg) during thyroid hormone synthesis. Thyroid follicles (the functional units of the thyroid) also utilize incompletely understood autoregulatory mechanisms to defend against exposure to excess iodide. To date, no transcriptomic studies have investigated these phenomena in vivo. Nuclear erythroid factor 2 like 2 (Nrf2 or Nfe2l2) is a transcription factor that regulates the expression of numerous antioxidant and other cytoprotective genes. We showed previously that the Nrf2 pathway regulates the antioxidant defense of follicular cells, as well as Tg transcription and Tg iodination. We, thus, hypothesized that Nrf2 might be involved in the transcriptional response to iodide overload. Methods: C57BL6/J wild-type (WT) or Nrf2 knockout (KO) male mice were administered regular water or water supplemented with 0.05% sodium iodide for seven days. RNA from their thyroids was prepared for next-generation RNA sequencing (RNA-Seq). Gene expression changes were assessed and pathway analyses were performed on the sets of differentially expressed genes. Results: Analysis of differentially expressed messenger RNAs (mRNAs) indicated that iodide overload upregulates inflammatory-, immune-, fibrosis- and oxidative stress-related pathways, including the Nrf2 pathway. Nrf2 KO mice showed a more pronounced inflammatory–autoimmune transcriptional response to iodide than WT mice. Compared to previously published datasets, the response patterns observed in WT mice had strong similarities with the patterns typical of Graves’ disease and papillary thyroid carcinoma (PTC). Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) also responded to iodide overload, with the latter targeting mRNAs that participate mainly in inflammation pathways. Conclusions: Iodide overload induces the Nrf2 cytoprotective response and upregulates inflammatory, immune, and fibrosis pathways similar to autoimmune hyperthyroidism (Graves’ disease) and PTC.

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Section: Discussionmentioning

confidence: 99%

The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System

Chartoumpekis

Ziros

Georgakopoulos-Soares

et al. 2020

Antioxidants

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“…Normalization of miR-22–3p (PerfeCTa microRNA assay) was performed against human or mouse RNU6 (PerfeCTa microRNA assay). Total RNA was also used for in-house small RNA library preparation and miRNA sequence profiling as previously described [ 25 ]. The resulting FASTQ files were demultiplexed, mapped, and annotated using a published pipeline [ 26 ].…”

Section: Methodsmentioning

confidence: 99%

Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent

Azar

Udi

Drori

et al. 2020

Molecular Metabolism

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Objective The endocannabinoid (eCB) system is increasingly recognized as being crucially important in obesity-related hepatic steatosis. By activating the hepatic cannabinoid-1 receptor (CB 1 R), eCBs modulate lipogenesis and fatty acid oxidation. However, the underlying molecular mechanisms are largely unknown. Methods We combined unbiased bioinformatics techniques, mouse genetic manipulations, multiple pharmacological, molecular, and cellular biology approaches, and genomic sequencing to systematically decipher the role of the hepatic CB 1 R in modulating fat utilization in the liver and explored the downstream molecular mechanisms. Results Using an unbiased normalized phylogenetic profiling analysis, we found that the CB 1 R evolutionarily coevolves with peroxisome proliferator-activated receptor-alpha (PPARα), a key regulator of hepatic lipid metabolism. In diet-induced obese (DIO) mice, peripheral CB 1 R blockade (using AM6545) induced the reversal of hepatic steatosis and improved liver injury in WT, but not in PPARα −/− mice. The antisteatotic effect mediated by AM6545 in WT DIO mice was accompanied by increased hepatic expression and activity of PPARα as well as elevated hepatic levels of the PPARα-activating eCB-like molecules oleoylethanolamide and palmitoylethanolamide. Moreover, AM6545 was unable to rescue hepatic steatosis in DIO mice lacking liver sirtuin 1 (SIRT1), an upstream regulator of PPARα. Both of these signaling molecules were modulated by the CB 1 R as measured in hepatocytes exposed to lipotoxic conditions or treated with CB 1 R agonists in the absence/presence of AM6545. Furthermore, using microRNA transcriptomic profiling, we found that the CB 1 R regulated the hepatic expression, acetylation, and transcriptional activity of p53, resulting in the enhanced expression of miR-22, which was found to specifically target SIRT1 and PPARα. Conclusions We provide strong evidence for a functional role of the p53/miR-22/SIRT1/PPARα signaling pathway in potentially mediating the antisteatotic effect of peripherally restricted CB 1 R blockade.

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“…In this case, molecular testing to detect specific gene mutations and gene rearrangements aimed at identifying malignancy can represent an opportunity. Although molecular testing are showing great promise in reducing the diagnostic uncertainty of cytologically indeterminate thyroid nodules, reducing the surgical rates for these lesions remain too expensive on the routine clinical management for a part of laboratories till today [8,[18][19][20][21][22]. e role of serum thyreotropin levels in the development and/or progression of thyroid cancer remains controversial.…”

Section: Discussionmentioning

confidence: 99%

Could Serum TSH Levels Predict Malignancy in Euthyroid Patients Affected by Thyroid Nodules with Indeterminate Cytology?

Cappelli

Pirola

Gandossi

et al. 2020

International Journal of Endocrinology

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Background. Serum TSH levels in the upper-normal range were reported to be associated with increased risk of thyroid malignancy. However, measurement of TSH levels is currently not recommended for assessing the risk of malignancy in patients with newly diagnosed thyroid nodules. Objective. To evaluate a possible relationship between the serum levels of TSH and the histological outcome of patients undergoing thyroidectomy for thyroid nodules with indeterminate cytology. Materials and Methods. We collected the clinical data of all patients who had performed ultrasound-guided FNA of thyroid nodules with cytological diagnosis of indeterminate lesions (TIR3A and TIR3B) and serum TSH levels within the normal range. All patients had been submitted to thyroid surgery (hemi or thyroidectomy, as appropriate), and histological diagnosis had been performed. Results. A histological diagnosis of thyroid malignancy was rendered in 74/378 (19.6%) nodules. Patients with histologically proven thyroid malignancy were characterized by higher serum levels of TSH as compared to patients with histologically proven benign nodules (3.03 ± 1.16 vs. 2.37 ± 1.19 mIU/L, p<0.001). To further analyze the role of serum TSH in predicting thyroid cancer, patients were stratified in 4 groups according to quartiles of TSH concentrations. The prevalence of malignancy was 12.2% for the first quartile and 50.0% for the last quartile. ROC curve analysis identified that a serum TSH level of ≥2.7 mIU/L predicted thyroid malignancy with a sensitivity of 61% and a specificity of 65%. Conclusions. TSH levels in the upper-normal range are associated with an increased risk of thyroid malignancy in patients affected by thyroid nodules with indeterminate cytology at FNA. The measurement of serum TSH levels represents an easily performed additional tool for decision-making in patients with indeterminate cytological findings.

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Next-Generation Sequencing Identifies a Highly Accurate miRNA Panel That Distinguishes Well-Differentiated Thyroid Cancer from Benign Thyroid Nodules

Cited by 28 publications

References 21 publications

The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System

The Transcriptomic Response of the Murine Thyroid Gland to Iodide Overload and the Role of the Nrf2 Antioxidant System

Reversal of diet-induced hepatic steatosis by peripheral CB1 receptor blockade in mice is p53/miRNA-22/SIRT1/PPARα dependent

Could Serum TSH Levels Predict Malignancy in Euthyroid Patients Affected by Thyroid Nodules with Indeterminate Cytology?

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