Testicular Orphan Receptor 4 (TR4) Promotes Papillary Thyroid Cancer Invasion via Activating Circ-FNLA/miR-149-5p/MMP9 Signaling

Abstract Background: The incidence and mortality of papillary thyroid cancer (PTC) have steadily increased. Although conventional therapies are very effective towards differentiated PTC patients, very limited therapeutic options are applicable to those patients with distant metastases. Therefore, better understanding of the molecular biology of metastatic PTC helps identify novel targets and facilitates the development of new therapies.Methods: Western blot assay was used to check relative gene protein expression. Transwell invasion assay was used to check the invasion capacity of the PTC cells. Wound healing assay was conducted to check the migration capacity of the PTC cells. qRT-PCR assay was used to check relative RNA expression of the cells. IHC assay was used to check TR4 and MMP9 expression in clinical samples or mouse tumor samples. Results: In this study, we first found that testicular orphan receptor 4 (TR4) was significantly increased in PTC tumors spreading to lymph node compared to the paired primary tumors. Experimental evidence suggested that TR4 drove PTC progression via promoting its cell invasion and cell migration. Mechanistically, TR4 transcriptionally regulated the expression level of circ-FLNA, which competed with MMP9 for miR-149-5p binding and led to increased protein level of MMP9. Interruption assays with various gene manipulations verified that TR4/circ-FLNA/miR-149-5p/MMP9 signaling axis played central role in cell invasion and cell migration of PTC cells. Moreover, xenografted mouse model also confirmed that TR4/circ-FLNA signal promoted PTC tumor growth.Conclusions: Overall, our study pinpoints the oncogenic role of TR4 in PTC development and targeting TR4/circ-FLNA/miR-149-5p/MMP9 signaling may be an alternative option for metastatic PTC patients.

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Detection of BRAFV600E in Liquid Biopsy from Patients with Papillary Thyroid Cancer Is Associated with Tumor Aggressiveness and Response to Therapy

Journal of Clinical Medicine ◽

10.3390/jcm9082481 ◽

2020 ◽

Vol 9 (8) ◽

pp. 2481

Author(s):

Kirk Jensen ◽

Shilpa Thakur ◽

Aneeta Patel ◽

Maria Cecilia Mendonca-Torres ◽

John Costello ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Liquid Biopsy ◽

Digital Pcr ◽

Response To Therapy ◽

Response To Treatment ◽

Papillary Thyroid ◽

Primary Tumors ◽

Promising Tool ◽

Increased Risk

The detection of rare mutational targets in plasma (liquid biopsy) has emerged as a promising tool for the assessment of patients with cancer. We determined the presence of cell-free DNA containing the BRAFV600E mutations (cfBRAFV600E) in plasma samples from 57 patients with papillary thyroid cancer (PTC) with somatic BRAFV600E mutation-positive primary tumors using microfluidic digital PCR, and co-amplification at lower denaturation temperature (COLD) PCR. Mutant cfBRAFV600E alleles were detected in 24/57 (42.1%) of the examined patients. The presence of cfBRAFV600E was significantly associated with tumor size (p = 0.03), multifocal patterns of growth (p = 0.03), the presence of extrathyroidal gross extension (p = 0.02) and the presence of pulmonary micrometastases (p = 0.04). In patients with low-, intermediate- and high-risk PTCs, cfBRAFV600E was detected in 4/19 (21.0%), 8/22 (36.3%) and 12/16 (75.0%) of cases, respectively. Patients with detectable cfBRAFV600E were characterized by a 4.68 times higher likelihood of non-excellent response to therapy, as compared to patients without detectable cfBRAFV600E (OR (odds ratios), 4.68; 95% CI (confidence intervals)) 1.26–17.32; p = 0.02). In summary, the combination of digital polymerase chain reaction (dPCR) with COLD-PCR enables the detection of BRAFV600E in the liquid biopsy from patients with PTCs and could prove useful for the identification of patients with PTC at an increased risk for a structurally or biochemically incomplete or indeterminate response to treatment.

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LncRNA CASC2 expression is down- regulated in papillary thyroid cancer and promotes cell invasion by affecting EMT pathway

Cancer Biomarkers ◽

10.3233/cbm-181198 ◽

2018 ◽

Vol 23 (2) ◽

pp. 185-191 ◽

Cited By ~ 13

Author(s):

Tao Zhou ◽

Meijun Zhong ◽

Shuyong Zhang ◽

Zhi Wang ◽

Rong Xie ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Cell Invasion ◽

Papillary Thyroid

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The molecular and gene/miRNA expression profiles of radioiodine resistant papillary thyroid cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-020-01757-x ◽

2020 ◽

Vol 39 (1) ◽

Author(s):

Carla Colombo ◽

Emanuela Minna ◽

Chiara Gargiuli ◽

Marina Muzza ◽

Matteo Dugo ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Mirna Expression ◽

Expression Profiles ◽

Expression Patterns ◽

Tissue Type ◽

Molecular Profile ◽

Papillary Thyroid ◽

Primary Tumors ◽

Disease Persistence

Abstract Background Papillary thyroid cancer (PTC) is the most frequent endocrine tumor. Radioiodine (RAI) treatment is highly effective in these tumors, but up to 60% of metastatic cases become RAI-refractory. Scanty data are available on either the molecular pattern of radioiodine refractory papillary thyroid cancers (PTC) or the mechanisms responsible for RAI resistance. Methods We analyzed the molecular profile and gene/miRNA expression in primary PTCs, synchronous and RAI-refractory lymph node metastases (LNMs) in correlation to RAI avidity or refractoriness. We classified patients as RAI+/D+ (RAI uptake/disease persistence), RAI−/D+ (absent RAI uptake/disease persistence), and RAI+/D- (RAI uptake/disease remission), and analyzed the molecular and gene/miRNA profiles, and the expression of thyroid differentiation (TD) related genes. Results A different molecular profile according to the RAI class was observed: BRAFV600E cases were more frequent in RAI−/D+ (P = 0.032), and fusion genes in RAI+/D+ cases. RAI+/D- patients were less frequently pTERT mutations positive, and more frequently wild type for the tested mutations/fusions. Expression profiles clearly distinguished PTC from normal thyroid. On the other hand, in refractory cases (RAI+/D+ and RAI−/D+) no distinctive PTC expression patterns were associated with either tissue type, or RAI uptake, but with the driving lesion and BRAF−/RAS-like subtype. Primary tumors and RAI-refractory LNMs with BRAFV600E mutation display transcriptome similarity suggesting that RAI minimally affects the expression profiles of RAI-refractory metastases. Molecular profiles associated with the expression of TPO, SLC26A4 and TD genes, that were found more downregulated in BRAFV600E than in gene fusions tumors. Conclusions The present data indicate a different molecular profile in RAI-avid and RAI-refractory metastatic PTCs. Moreover, BRAFV600E tumors displayed reduced differentiation and intrinsic RAI refractoriness, while PTCs with fusion oncogenes are RAI-avid but persistent, suggesting different oncogene-driven mechanisms leading to RAI refractoriness.

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