scholarly journals Inhibition of STAT3 activity delays obesity-induced thyroid carcinogenesis in a mouse model

2015 ◽  
Vol 23 (1) ◽  
pp. 53-63 ◽  
Author(s):  
Jeong Won Park ◽  
Cho Rong Han ◽  
Li Zhao ◽  
Mark C Willingham ◽  
Sheue-yann Cheng
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Specific Inhibitor ◽  
Epidemiologic Studies ◽  
Thyroid Tumor ◽  
Obesity Prevalence ◽  
Marked Rise ◽  
Mesenchymal Transition

Compelling epidemiologic studies indicate that obesity is a risk factor for many human cancers, including thyroid cancer. In recent decades, the incidence of thyroid cancer has dramatically increased along with a marked rise in obesity prevalence. We previously demonstrated that a high fat diet (HFD) effectively induced the obese phenotype in a mouse model of thyroid cancer (ThrbPV/PVPten+/− mice). Moreover, HFD activates the STAT3 signal pathway to promote more aggressive tumor phenotypes. The aim of the present study was to evaluate the effect of S3I-201, a specific inhibitor of STAT3 activity, on HFD-induced aggressive cancer progression in the mouse model of thyroid cancer. WT and ThrbPV/PVPten+/− mice were treated with HFD together with S3I-201 or vehicle-only as controls. We assessed the effects of S3I-201 on HFD-induced thyroid cancer progression, the leptin-JAK2-STAT3 signaling pathway, and key regulators of epithelial-mesenchymal transition (EMT). S3I-201 effectively inhibited HFD-induced aberrant activation of STAT3 and its downstream targets to markedly inhibit thyroid tumor growth and to prolong survival. Decreased protein levels of cyclins D1 and B1, cyclin dependent kinase 4 (CDK4), CDK6, and phosphorylated retinoblastoma protein led to the inhibition of tumor cell proliferation in S3I-201-treated ThrbPV/PVPten+/− mice. Reduced occurrence of vascular invasion and blocking of anaplasia and lung metastasis in thyroid tumors of S3I-201-treated ThrbPV/PVPten+/− mice were mediated via decreased expression of vimentin and matrix metalloproteinases, two key effectors of EMT. The present findings suggest that inhibition of the STAT3 activity would be a novel treatment strategy for obesity-induced thyroid cancer.

scholarly journals Osteopontin Expression in Thyroid Cancer: Deciphering EMT-Related Molecular Mechanisms

Biomedicines ◽  
2021 ◽  
Vol 9 (10) ◽  
pp. 1372
Author(s):  
Bruna Prunes Pena Baroni Viana ◽  
Amanda Vitória Pampolha Gomes ◽  
Etel Rodrigues Pereira Gimba ◽  
Luciana Bueno Ferreira
Keyword(s):  
Thyroid Cancer ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Endocrine System ◽  
Good Prognosis ◽  
Thyroid Tumor ◽  
Diagnostic Tools ◽  
Matricellular Protein ◽  
Mesenchymal Transition

Thyroid cancer is the most common tumor arising from the endocrine system and generally presents good prognosis. However, its aggressive subtypes are related to therapeutic resistance and early metastasis. Epithelial–mesenchymal transition (EMT) and its reverse process, the mesenchymal–epithelial transition (MET), are key events mediating cancer progression, including in thyroid cancer. The matricellular protein osteopontin (OPN) has been reported as a master regulator of EMT in many tumor types. Although high OPN expression has been described and associated with important aspects of thyroid cancer progression, there is no clear evidence regarding OPN as a regulator of EMT in thyroid cancer. Thus, taking together the known roles of OPN in the modulation of EMT in cancer and the information reporting the expression of OPN in thyroid tumor progression, this review aims at summarizing and discussing data related to EMT in thyroid cancer and its putative relation to the roles of OPN in the development of thyroid cancer. These data provide new insights into the molecular mechanisms by which OPN could potentially modulate EMT in thyroid tumors, generating evidence for future studies that may contribute to new therapeutic, prognostic and/or diagnostic tools.

scholarly journals YDJC Induces Epithelial-Mesenchymal Transition via Escaping from Interaction with CDC16 through Ubiquitination of PP2A

2019 ◽  
Vol 2019 ◽  
pp. 1-15 ◽  
Author(s):  
Eun Ji Kim ◽  
Mi Kyung Park ◽  
Gyeoung-Jin Kang ◽  
Hyun Jung Byun ◽  
Hyun Ji Kim ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mouse Model ◽  
Cancer Progression ◽  
Epithelial Mesenchymal Transition ◽  
Term Treatment ◽  
Orthotopic Mouse Model ◽  
Mesenchymal Transition ◽  
Long Term Treatment ◽  
Phosphatase 2A

Lung cancer is the number 1 cause of cancer-related casualties in the world. Appropriate diagnostic markers and novel targets for lung cancer are needed. Chitooligosaccharide deacetylase homolog (YDJC) catalyzes the deacetylation of acetylated carbohydrates; however, the role of YDJC in lung cancer progression has yet to be studied. A549 lung cancer orthotopic mouse model was used for mice experiments. We found that YDJC overexpression contributes to lung cancer progression in an orthotopic mouse model. Long-term treatment (48 h) induces YDJC expression in sphingosylphosphorylcholine (SPC)-induced epithelial-mesenchymal transition (EMT). Gene silencing of YDJC (siYDJC) reduced N-cadherin expression and increased E-cadherin expression in SPC-induced EMT. Overexpression of YDJC reverses them but overexpression of the deacetylase deficient mutant YDJCD13A could not. Interestingly, overexpression of CDC16, a YDJC binding partner, suppressed EMT. ERK2 is activated in siCDC16-induced EMT. YDJC overexpression reduces expression of protein phosphatase 2A (PP2A), whereas CDC16 overexpression induces PP2A expression. YDJC overexpression induced ubiquitination of PP2A but YDJCD13A could not. CDC16 overexpression increased the ubiquitination of YDJC. These results suggest that YDJC contributes to the progression of lung cancer via enhancing EMT by inducing the ubiquitination of PP2A. Therefore, YDJC might be a new target for antitumor therapy against lung cancer.

scholarly journals Expression and Clinical Utility of Transcription Factors Involved in Epithelial–Mesenchymal Transition during Thyroid Cancer Progression

2021 ◽  
Vol 10 (18) ◽  
pp. 4076
Author(s):  
Enke Baldini ◽  
Chiara Tuccilli ◽  
Daniele Pironi ◽  
Antonio Catania ◽  
Francesco Tartaglia ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Thyroid Cancer ◽  
Cancer Progression ◽  
Clinical Utility ◽  
Epithelial Mesenchymal Transition ◽  
Clinicopathological Parameters ◽  
Mrna Levels ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
E Cadherin

The transcription factors involved in epithelial–mesenchymal transition (EMT-TFs) silence the genes expressed in epithelial cells (e.g., E-cadherin) while inducing those typical of mesenchymal cells (e.g., vimentin). The core set of EMT-TFs comprises Zeb1, Zeb2, Snail1, Snail2, and Twist1. To date, information concerning their expression profile and clinical utility during thyroid cancer (TC) progression is still incomplete. We evaluated the EMT-TF, E-cadherin, and vimentin mRNA levels in 95 papillary TC (PTC) and 12 anaplastic TC (ATC) tissues and correlated them with patients’ clinicopathological parameters. Afterwards, we corroborated our findings by analyzing the data provided by a case study of the TGCA network. Compared with normal tissues, the expression of E-cadherin was found reduced in PTC and more strongly in ATC, while the vimentin expression did not vary. Among the EMT-TFs analyzed, Twist1 seems to exert a prominent role in EMT, being significantly associated with a number of PTC high-risk clinicopathological features and upregulated in ATC. Nonetheless, in the multivariate analysis, none of the EMT-TFs displayed a prognostic value. These data suggest that TC progression is characterized by an incomplete EMT and that Twist1 may represent a valuable therapeutic target warranting further investigation for the treatment of more aggressive thyroid cancers.

scholarly journals Multifunctional Roles of miR-34a in Cancer: A Review with the Emphasis on Head and Neck Squamous Cell Carcinoma and Thyroid Cancer with Clinical Implications

Diagnostics ◽  
2020 ◽  
Vol 10 (8) ◽  
pp. 563
Author(s):  
David Kalfert ◽  
Marie Ludvikova ◽  
Martin Pesta ◽  
Jaroslav Ludvik ◽  
Lucie Dostalova ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Head And Neck ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Current Knowledge ◽  
Human Cancer ◽  
Squamous Carcinoma ◽  
Transcriptional Level ◽  
Mesenchymal Transition

MiR-34a belongs to the class of small non-coding regulatory RNAs and functions as a tumor suppressor. Under physiological conditions, miR-34a has an inhibitory effect on all processes related to cell proliferation by targeting many proto-oncogenes and silencing them on the post-transcriptional level. However, deregulation of miR-34a was shown to play important roles in tumorigenesis and processes associated with cancer progression, such as tumor-associated epithelial-mesenchymal transition, invasion, and metastasis. Moreover, further understanding of miR-34a molecular mechanisms in cancer are indispensable for the development of effective diagnosis and treatments. In this review, we summarized the current knowledge on miR-34a functions in human disease with an emphasis on its regulation and dysregulation, its role in human cancer, specifically head and neck squamous carcinoma and thyroid cancer, and emerging role as a disease diagnostic and prognostic biomarker and the novel therapeutic target in oncology.

scholarly journals Metformin and JQ1 synergistically inhibit obesity-activated thyroid cancer

2018 ◽  
Vol 25 (10) ◽  
pp. 865-877 ◽  
Author(s):  
Sunmi Park ◽  
Mark C Willingham ◽  
Jun Qi ◽  
Sheue-Yann Cheng
Keyword(s):  
Thyroid Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Cancer Progression ◽  
High Fat Diet ◽  
Combined Treatment ◽  
Thyroid Tumor ◽  
Molecular Evidence ◽  
Strong Positive Correlation ◽  
High Fat

Compelling epidemiological evidence shows a strong positive correlation of obesity with thyroid cancer.In vivostudies have provided molecular evidence that high-fat-diet-induced obesity promotes thyroid cancer progression by aberrantly activating leptin-JAK2-STAT3 signaling in a mouse model of thyroid cancer (ThrbPV/PVPten+/−mice). TheThrbPV/PVPten+/−mouse expresses a dominantly negative thyroid hormone receptor β (denoted as PV) and a deletion of one single allele of thePtengene. TheThrbPV/PVPten+/−mouse spontaneously develops follicular thyroid cancer, which allows its use as a preclinical mouse model to test potential therapeutics. We recently showed that inhibition of STAT3 activity by a specific inhibitor markedly delays thyroid cancer progression in high-fat-diet-induced obeseThrbPV/PVPten+/−mice (HFD-ThrbPV/PVPten+/−mice). Further, metformin, a widely used antidiabetic drug, blocks invasion and metastasis, but not thyroid tumor growth in HFD-ThrbPV/PVPten+/−mice. To improve efficacy in reducing thyroid tumor growth, we treated HFD-ThrbPV/PVPten+/−with JQ1, a potent inhibitor of the activity of bromodomain and extraterminal domain (BET) and with metformin. We found that the combined treatment synergistically suppressed thyroid tumor growth by attenuating STAT3 and ERK signaling, resulting in decreased anti-apoptotic key regulators such as Mcl-1, Bcl-2 and survivin and increased pro-apoptotic regulators such as Bim, BAD and cleave caspase 3. Furthermore, combined treatment of JQ1 and metformin reduced cMyc protein levels to suppress vascular invasion, anaplasia and lung metastasis. These findings indicate that combined treatment is more effective than metformin alone and suggest a novel treatment modality for obesity-activated thyroid cancer.

scholarly journals MicroRNA Deregulation in Anaplastic Thyroid Cancer Biology

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Cesar Seigi Fuziwara ◽  
Edna Teruko Kimura
Keyword(s):  
Thyroid Cancer ◽  
Tumor Suppressor ◽  
Cancer Progression ◽  
Cell Biology ◽  
Cancer Biology ◽  
Anaplastic Thyroid Cancer ◽  
Genetic Alterations ◽  
Thyroid Tumor ◽  
Mesenchymal Transition ◽  
Promising Therapeutic Approach

Anaplastic thyroid cancer (ATC) is among the most lethal types of cancers, characterized as a fast-growing and highly invasive thyroid tumor that is unresponsive to surgery and radioiodine, blunting therapeutic efficacy. Classically, genetic alterations in tumor suppressorTP53are frequent, and cumulative alterations in different signaling pathways, such as MAPK and PI3K, are detected in ATC. Recently, deregulation in microRNAs (miRNAs), a class of small endogenous RNAs that regulate protein expression, has been implicated in tumorigenesis and cancer progression. Deregulation of miRNA expression is detected in thyroid cancer. Upregulation of miRNAs, such asmiR-146b,miR-221, andmiR-222, is observed in ATC and also in differentiated thyroid cancer (papillary and follicular), indicating that these miRNAs’ overexpression is essential in maintaining tumorigenesis. However, specific miRNAs are downregulated in ATC, such as those of themiR-200andmiR-30families, which are important negative regulators of cell migration, invasion, and epithelial-to-mesenchymal transition (EMT), processes that are overactivated in ATC. Therefore, molecular interference to restore the expression of tumor suppressor miRNAs, or to blunt overexpressed oncogenic miRNAs, is a promising therapeutic approach to ameliorate the treatment of ATC. In this review, we will explore the importance of miRNA deregulation for ATC cell biology.

scholarly journals The Aryl Hydrocarbon Receptor Is Expressed in Thyroid Carcinoma and Appears to Mediate Epithelial-Mesenchymal-Transition

Cancers ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 145 ◽  
Author(s):  
Sonia Moretti ◽  
Nicole Nucci ◽  
Elisa Menicali ◽  
Silvia Morelli ◽  
Vittorio Bini ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Motility ◽  
Aryl Hydrocarbon Receptor ◽  
Cancer Progression ◽  
Target Genes ◽  
Epithelial Mesenchymal Transition ◽  
Receptor Activation ◽  
Mesenchymal Transition ◽  
Aryl Hydrocarbon ◽  
And Migration

Aryl hydrocarbon receptor (AhR) is expected to promote initiation, progression and invasion of cancer cells regulating proliferation, differentiation, gene expression, inflammation, cell motility and migration. Furthermore, an immunosuppressant function of AhR has been recognized. This study evaluated AhR expression and its role in thyroid cancer progression. AhR expression was assessed by qPCR in 107 thyroid cancer samples (90 PTCs, 11 MTCs, 6 ATCs), and by immunohistochemistry in 41 PTCs. To estimate receptor activation, the expression of target genes CYP1A1 and CYP1B1 was measured. AhR functional effects were evaluated in kynurenine-stimulated FTC-133 and BcPap cell lines by analyzing the expression of genes involved in EMT and cell motility. AhR mRNA expression resulted significantly higher in all the analyzed thyroid cancer samples compared to normal thyroid and a statistically significant correlation with CYP1B1 was detected. Kynurenine-stimulated FTC-133 and BcPap showed the activation of a specific AhR-driven EMT program characterized by E-cadherin decrease and SLUG, N-cadherin and fibronectin increase, resulting in boost of cell motility and invasion. This study confirmed the importance of the IDO1-Kyn-AhR pathway in thyroid cancer tumorigenesis, suggesting an AhR pivotal role in mediating an immunosuppressive microenvironment and favoring the acquisition of a mesenchymal phenotype that could promote invasiveness and metastasis.

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