The role of the transcription factor - Prospero homeobox 1 (Prox1) in the biology of differentiated thyroid cancer - the effect of the expression of Prox1 on migration and invasiveness of thyroid cancer cells

Context: ZIC1 has been reported to be overexpressed and plays an oncogenic role in some brain tumors, whereas it is inactivated by promoter hypermethylation and acts as a tumor suppressor in gastric and colorectal cancers. However, until now, its biological role in thyroid cancer remains totally unknown. Objectives: The aim of this study is to explore the biological functions and related molecular mechanism of ZIC1 in thyroid carcinogenesis. Setting and Design: Quantitative RT-PCR (qRT-PCR) was performed to evaluate mRNA expression of investigated genes. Methylation-specific PCR was used to analyze promoter methylation of the ZIC1 gene. The functions of ectopic ZIC1 expression in thyroid cancer cells were determined by cell proliferation and colony formation, cell cycle and apoptosis, as well as cell migration and invasion assays. Results: ZIC1 was frequently down-regulated by promoter hypermethylation in both primary thyroid cancer tissues and thyroid cancer cell lines. Moreover, our data showed that ZIC1 hypermethylation was significantly associated with lymph node metastasis in patients with papillary thyroid cancer. Notably, restoration of ZIC1 expression in thyroid cancer cells dramatically inhibited cell proliferation, colony formation, migration and invasion, and induced cell cycle arrest and apoptosis by blocking the activities of the phosphatidylinositol-3-kinase (PI3K)/Akt and RAS/RAF/MEK/ERK (MAPK) pathways, and enhancing FOXO3a transcriptional activity. Conclusions: Our data demonstrate that ZIC1 is frequently inactivated by promoter hypermethyaltion and functions as a tumor suppressor in thyroid cancer through modulating PI3K/Akt and MAPK signaling pathways and transcription factor FOXO3a.

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Crosstalk Between Abnormal TSHR Signaling Activation and PTEN/PI3K in the Dedifferentiation of Thyroid Cancer Cells

Frontiers in Oncology ◽

10.3389/fonc.2021.718578 ◽

2021 ◽

Vol 11 ◽

Author(s):

Fang Feng ◽

Huiqin Han ◽

Shuqi Wu ◽

Hui Wang

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Mtor Signaling ◽

Iodide Uptake ◽

Thyroid Cells ◽

Cell Mobility ◽

Signaling Activation ◽

Thyroid Cancer Cells ◽

Serum Tsh

Iodide uptake and the metabolism of thyroid cells are regulated by thyrotropin (TSH)-TSH receptor (TSHR) signaling. Thus, it is necessary to elevate serum TSH levels by T4 withdraw or rTSH administration to facilitate radioiodide (131I) therapy for differentiated thyroid cancer (DTC). However, non-iodide-avid metastases of DTC which is dedifferentiated do not respond to stimulation by high levels of TSH, suggesting abnormal TSH-TSHR signal transduction in cancer cells. In addition, PI3K/AKT/mTOR signaling activation has been shown to be associated with the dedifferentiated phenotype of thyroid cancer, but the mechanism remains elusive. Therefore, in this study, we aimed to explore the role of abnormal TSH-TSHR signaling activation in regulating iodide uptake and cell mobility in thyroid cancer and its relationship with PI3K/AKT/mTOR signaling. We found that in thyroid cancer cells, TSH binds TSHR coupled to the Gα12/13 protein and then activates RhoA through interacting with leukemia associated RhoA guanine exchange factor (LARG). This results in a promigration tumorigenic phenotype independent of canonical TSHR-GαS signaling that regulates the expression of molecules involved in iodine uptake and metabolism. We observed that signaling pathways downstream of Gα12/13 signaling were increased, while that of Gαs signaling was decreased in thyroid cancer cells undergoing dedifferentiation compared to control cells following stimulation with different levels of TSH. PI3K/AKT/mTOR signaling activation enhanced Gα12/13 signaling through increasing LARG levels but also inhibited the expression of molecules downstream of Gαs signaling, including thyroid-specific molecules, and iodide uptake. In summary, our results demonstrate the noncanonical activation of TSH-TSHR signaling and its role in increasing the cell mobility and dedifferentiation of thyroid cancer through crosstalk with PI3K/AKT/mTOR signaling.

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Adipogenic Differentiation of Thyroid Cancer Cells Through the Pax8-PPARγ Fusion Protein Is Regulated by Thyroid Transcription Factor 1 (TTF-1)

Journal of Biological Chemistry ◽

10.1074/jbc.m116.740324 ◽

2016 ◽

Vol 291 (37) ◽

pp. 19274-19286 ◽

Cited By ~ 5

Author(s):

Bin Xu ◽

Michael O'Donnell ◽

Jeffrey O'Donnell ◽

Jingcheng Yu ◽

Yanxiao Zhang ◽

...

Keyword(s):

Transcription Factor ◽

Thyroid Cancer ◽

Fusion Protein ◽

Cancer Cells ◽

Adipogenic Differentiation ◽

Thyroid Transcription Factor 1 ◽

Thyroid Transcription Factor ◽

Transcription Factor 1 ◽

Thyroid Cancer Cells

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Salidroside inhibits migration and invasion of poorly differentiated thyroid cancer cells

Thoracic Cancer ◽

10.1111/1759-7714.13096 ◽

2019 ◽

Vol 10 (6) ◽

pp. 1469-1478

Author(s):

Hongxia Shang ◽

Shengnan Wang ◽

Jinming Yao ◽

Congcong Guo ◽

Jianjun Dong ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Differentiated Thyroid Cancer ◽

Migration And Invasion ◽

Poorly Differentiated ◽

Thyroid Cancer Cells

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Spheroid formation of human thyroid cancer cells under simulated microgravity: a possible role of CTGF and CAV1

Cell Communication and Signaling ◽

10.1186/1478-811x-12-32 ◽

2014 ◽

Vol 12 (1) ◽

pp. 32 ◽

Cited By ~ 45

Author(s):

Elisabeth Warnke ◽

Jessica Pietsch ◽

Markus Wehland ◽

Johann Bauer ◽

Manfred Infanger ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Simulated Microgravity ◽

Human Thyroid ◽

Spheroid Formation ◽

Thyroid Cancer Cells

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Effects of sorafenib and an adenylyl cyclase activator on in vitro growth of well-differentiated thyroid cancer cells

Endocrine Journal ◽

10.1507/endocrj.ej16-0525 ◽

2017 ◽

Vol 64 (11) ◽

pp. 1115-1123 ◽

Cited By ~ 3

Author(s):

Aya Sawa ◽

Tomohiro Chiba ◽

Jun Ishii ◽

Hiroyuki Yamamoto ◽

Hisato Hara ◽

...

Keyword(s):

Thyroid Cancer ◽

Adenylyl Cyclase ◽

Cancer Cells ◽

Differentiated Thyroid Cancer ◽

Well Differentiated ◽

Thyroid Cancer Cells ◽

Cyclase Activator

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The role of human achaete-scute homolog-1 in medullary thyroid cancer cells

Surgery ◽

10.1016/s0039-6060(03)00418-5 ◽

2003 ◽

Vol 134 (6) ◽

pp. 866-871 ◽

Cited By ~ 45

Author(s):

Rebecca S Sippel ◽

Jennifer E Carpenter ◽

Muthusamy Kunnimalaiyaan ◽

Herbert Chen

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Medullary Thyroid Cancer ◽

Medullary Thyroid ◽

Thyroid Cancer Cells

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miR-32-5p Inhibits the Proliferation, Migration and Invasion of Thyroid Cancer Cells by Regulating Twist1

10.21203/rs.3.rs-552882/v1 ◽

2021 ◽

Author(s):

Qing Liu ◽

Ouyang Li ◽

Chi Zhou ◽

Yu Wang ◽

Chunxue He ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Transition Process ◽

Underlying Mechanism ◽

Luciferase Assay ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Thyroid Cancer Cells

Abstract Background: Thyroid cancer is the most prevalent malignancy and one of the leading causes of cancer-related deaths. Recent studies have revealed that microRNAs (miRNAs) play an important role in tumorigenesis in various cancer types by affecting the expression of its targets. However, the role of miR-32-5p in thyroid cancer remains limited. Methods: In this study, we attempt to explore the role of miR-32-5p in thyroid cancer and elucidate the underlying mechanism. Expression of miR-32-5p was determined by quantitative reverse transcription PCR. Functional assays were performed by CCK-8 assay, cell colony assay, cell apoptosis assay, cell migration and invasion assays, cell cycle assay and luciferase assay. Protein expression was analyzed by Western blot.Results: In the present study, the role of miR-32-5p in thyroid cancer was firstly explored. It is found that miR-32-5p was downregulated in thyroid cancer tissues and cells. Overexpression of miR-32-5p inhibited thyroid cancer cells proliferation, migration, invasion and epithelial‐mesenchymal transition process; while suppression of miR-32-5p exhibited an opposite effect on thyroid cancer cells. In addition, In addition, a luciferase assay showed Twist1 was identified as a direct target of miR-32-5p in thyroid cancer, and further study showed that restoration of Twist1 attenuated the biological effect of miR-32-5p on thyroid cancer cells. Conclusion: In conclusion, our results demonstrated miR-32-5p functions as a tumor suppressor by targeting Twist1 in thyroid cancer, providing a novel insight into thyroid cancer therapy.

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AUF1 Promotes Proliferation and Invasion of Thyroid Cancer via Downregulation of ZBTB2 and Subsequent TRIM58

Frontiers in Oncology ◽

10.3389/fonc.2021.681736 ◽

2021 ◽

Vol 11 ◽

Author(s):

Xin Du ◽

Jia-Mei Wang ◽

Da-Lin Zhang ◽

Tong Wu ◽

Xiao-Yan Zeng ◽

...

Keyword(s):

Thyroid Cancer ◽

Cancer Cells ◽

Binding Sites ◽

Critical Role ◽

Common Type ◽

Migration And Invasion ◽

Papillary Thyroid ◽

Thyroid Cancer Cells ◽

Proliferation And Invasion

The pathogenesis of papillary thyroid cancer (PTC), the most common type of thyroid cancer, is not yet fully understood. This limits the therapeutic options for approximately 7% of invasive PTC patients. The critical role of AUF1 in the progression of thyroid cancer was first reported in 2009, however, its molecular mechanism remained unclear. Our study used CRISPR/Cas 9 system to knockdown AUF1 in IHH4 and TPC1 cells. We noticed that the expression of TRIM58 and ZBTB2 were increased in the AUF1 knockdown IHH4 and TPC1 cells. When TRIM58 and ZBTB2 were inhibited by small hairpin RNAs (shRNAs) against TRIM58 (shTRIM58) and ZBTB2 (shZBTB2), respectively, the proliferation, migration, and invasion ability of the AUF1-knockdown IHH4 and TPC1 cells were increased. In addition, two ZBTB2 binding sites (-719~-709 and -677~-668) on TRIM58 promoter and two AUF1 binding sites (1250-1256 and 1258-1265) on ZBTB2 3’-UTR were identified. These results suggested that AUF1 affecting thyroid cancer cells via regulating the expression of ZBTB2 and TRIM58.

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