scholarly journals FOXM1 is a molecular determinant of the mitogenic and invasive phenotype of anaplastic thyroid carcinoma

2012 ◽  
Vol 19 (5) ◽  
pp. 695-710 ◽  
Author(s):  
Roberto Bellelli ◽  
Maria Domenica Castellone ◽  
Ginesa Garcia-Rostan ◽  
Clara Ugolini ◽  
Carmelo Nucera ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Cancer Progression ◽  
Target Genes ◽  
Cyclin B1 ◽  
Anaplastic Thyroid Carcinoma ◽  
Loss Of Function ◽  
Thyroid Carcinomas ◽  
Forkhead Box

Anaplastic thyroid carcinoma (ATC) is a very aggressive thyroid cancer. forkhead box protein M1 (FOXM1) is a member of the forkhead box family of transcription factors involved in control of cell proliferation, chromosomal stability, angiogenesis, and invasion. Here, we show that FOXM1 is significantly increased in ATCs compared with normal thyroid, well-differentiated thyroid carcinomas (papillary and/or follicular), and poorly differentiated thyroid carcinomas (P=0.000002). Upregulation of FOXM1 levels in ATC cells was mechanistically linked to loss-of-function of p53 and to the hyperactivation of the phosphatidylinositol-3-kinase/AKT/FOXO3a pathway. Knockdown of FOXM1 by RNA interference inhibited cell proliferation by arresting cells in G2/M and reduced cell invasion and motility. This phenotype was associated with decreased expression of FOXM1 target genes, like cyclin B1 (CCNB1), polo-like kinase 1 (PLK1), Aurora B (AURKB), S-phase kinase-associated protein 2 (SKP2), and plasminogen activator, urokinase: uPA (PLAU). Pharmacological inhibition of FOXM1 in an orthotopic mouse model of ATC reduced tumor burden and metastasization. All together, these findings suggest that FOXM1 represents an important player in thyroid cancer progression to the anaplastic phenotype and a potential therapeutic target for this fatal cancer.

scholarly journals Overexpression of NELFE contributes to gastric cancer progression via Wnt/β-catenin signaling-mediated activation of CSNK2B expression

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Shijun Yu ◽  
Li Li ◽  
Hui Cai ◽  
Bin He ◽  
Yong Gao ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cell Proliferation ◽  
Cancer Progression ◽  
Target Genes ◽  
Mrna Level ◽  
Luciferase Reporter ◽  
Migration And Invasion ◽  
Loss Of Function ◽  
Mice Model ◽  
Qrt Pcr

Abstract Background Accumulating evidence has highlighted the importance of negative elongation factor complex member E (NELFE) in tumorigenesis. However, the relationship between NELFE and gastric cancer (GC) remains unclear. This study aimed to explore the expression pattern and specific function of NELFE in GC. Methods NELFE expression was evaluated by immunohistochemistry and qRT-PCR in GC tissues, respectively. Cell proliferation, migration and invasion were measured by CCK-8, colony formation, transwell assays, and nude mice model. Bioinformatics analysis was performed to search potential target genes of NELFE, and a Cignal Finder 10-Pathway Reporter Array was used to explore potential signaling pathways regulated by NELFE. Dual-luciferase reporter assays, qRT-PCR and western blotting were conducted to verify their regulatory relationship. The expression correlations among NELFE, β-catenin and CSNK2B were further explored by immunohistochemistry on consecutive resections. Results NELFE was significantly overexpressed in GC tissues both in protein and mRNA level and negatively correlated with the prognosis of GC patients. Gain- and loss-of-function experiments showed that NELFE potentiated GC cell proliferation and metastasis in vitro and in vivo. CSNK2B was identified as a downstream effector of NELFE. Wnt/β-catenin signaling may mediate the regulation of CSNK2B by NELFE. In addition, NELFE, β-catenin and CSNK2B were all remarkably upregulated in tumor tissues compared with adjacent normal tissues, and their expression levels in GC were positively correlated with each other. Conclusion Our findings reveal a new NELFE-Wnt/β-catenin-CSNK2B axis to promote GC progression and provide new candidate targets against this disease.

scholarly journals IL13RA2 Is Differentially Regulated in Papillary Thyroid Carcinoma vs Follicular Thyroid Carcinoma

2019 ◽  
Vol 104 (11) ◽  
pp. 5573-5584 ◽  
Author(s):  
Siao Ting Chong ◽  
Khee Ming Tan ◽  
Catherine Y L Kok ◽  
Shou Ping Guan ◽  
Siang Hui Lai ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Migration ◽  
Thyroid Cancer ◽  
Papillary Thyroid Carcinoma ◽  
Thyroid Carcinoma ◽  
Cell Lines ◽  
Papillary Thyroid ◽  
Thyroid Carcinomas ◽  
Advanced Tumor

Abstract Context The interleukin-13 receptor alpha2 (IL13RA2), which is known to be overexpressed in glioblastoma multiforme, plays a role in various cellular processes such as cell migration that may contribute to tumor progression. Studies have attributed IL13RA2 to invasion and metastasis in cancers of the ovary, breast, and pancreas, but the pathological role of IL13RA2 in thyroid cancer is still unclear. Objective This study aims to evaluate IL13RA2 expression in thyroid carcinomas and to examine the role of IL13RA2 in the progression of papillary thyroid carcinoma (PTC). Methods IL13RA2 immunochemical staining was performed on tissue microarrays of 137 thyroid carcinomas from patients, and the differential profile of IL13RA2 was validated in thyroid cancer cell lines. In PTC cell lines, we functionally assessed the effects of IL13RA2 underexpression and overexpression on cell proliferation, cell migration, and epithelial-mesenchymal transition (EMT) by using CCK-8, transwell migration assay, quantitative RT-PCR, and Western blot analysis. Results IL13RA2 expression was significantly correlated with advanced tumor T stage (pT3 or pT4; P = 0.001) and regional lymph node metastasis (pN1; P < 0.001). The staining scores of IL13RA2 were significantly higher in PTC compared with follicular subtypes (P < 0.001) and correlated with advanced tumor stage among PTC samples (pT3 or pT4; P = 0.028). Knockdown of IL13RA2 in B-CPAP cells significantly reduced cell viability, cell migration, and EMT markers including N-cadherin, Vimentin, and Snail. Exogenous overexpression of IL13RA2 in K1 cells increased cell migration and EMT, although cell proliferation was not affected. Conclusion IL13RA2 is differentially regulated in PTC and is involved in cell migration by enhancing EMT.

scholarly journals MicroRNA-363-3p downregulation in papillary thyroid cancer inhibits tumor progression by targeting NOB1

2020 ◽  
Vol 69 (1) ◽  
pp. 66-74
Author(s):  
Su Dong ◽  
Shuai Xue ◽  
Yue Sun ◽  
Zhe Han ◽  
Lele Sun ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Tumor Progression ◽  
Papillary Thyroid Cancer ◽  
Cancer Progression ◽  
Migration And Invasion ◽  
Papillary Thyroid ◽  
Thyroid Cells

MicroRNA-363-3 p (miR-363–3 p) has been reported to play a crucial role in tumor development and progression, and function as a tumor suppressor in many types of cancer. In our previous studies, we found that miRNA-363–3 p inhibited papillary thyroid carcinoma (PTC) progression by targeting PIK3CA. Meanwhile, we found that NIN1/RPN12 binding protein 1 (NOB1) was significantly upregulated in thyroid carcinoma tissue and downregulation of NOB1 expression significantly inhibited cell proliferation, migration and invasion in PTC. However, the correlation of NOB1 and miR-363–3 p has not been investigated. Here, we performed bioinformatic analysis to explore miRNA targeting NOB1. We found that NOB1 was a target of miR-363–3 p and miR-363–3 p regulated NOB1 expression at the translational and transcriptional levels by targeting its 3’ untranslated region (3'-UTR). Further, we showed that miR-363–3 p inhibited tumor progression by targeting NOB1 in vitro and in vivo. We found that overexpression miR-363–3 p or silencing NOB1 significantly increased G0/G1-phase and decreased S-phase in the human papillary thyroid cells, which led to a significant delay in cell proliferation, indicating miR-363–3 p and NOB1 are crucial for human papillary thyroid cancer tumorigenesis. Collectively, our data unveil that miR-363–3 p negatively regulates NOB1 activity by reducing its stability. This study provides a new therapeutic target for regulation of NOB1 stability to modulate human papillary thyroid cancer progression.

scholarly journals Comprehensive screening for PD-L1 expression in thyroid cancer

2017 ◽  
Vol 24 (2) ◽  
pp. 97-106 ◽  
Author(s):  
Soomin Ahn ◽  
Tae Hyuk Kim ◽  
Sun Wook Kim ◽  
Chang Seok Ki ◽  
Hye Won Jang ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Thyroid Carcinoma ◽  
Disease Progression ◽  
Large Scale ◽  
Anaplastic Thyroid Carcinoma ◽  
Papillary Thyroid ◽  
Thyroid Cancers ◽  
Thyroid Carcinomas ◽  
Oncogenic Mutation ◽  
Potential Biomarker

PD-L1 expression is being considered a potential biomarker for response of anti-PD-1 or anti-PD-L1 agents in various tumors. The reported frequency of PD-L1 positivity varies in thyroid carcinomas, and multiple factors may contribute to the variability in PD-L1 positivity. We evaluated the PD-L1 expression in various thyroid cancers on a large scale. A total of 407 primary thyroid cancers with a median 13.7-year of follow-up were included. We evaluated the frequency of PD-L1 expression using a rabbit monoclonal antibody (clone SP142). In addition, we analyzed the relationships between PD-L1 expression and clinicopathologic factors, includingTERTpromoter, BRAFstatus and disease progression. Tumoral PD-L1 was expressed in 6.1% of papillary thyroid carcinomas, 7.6% of follicular thyroid carcinomas and 22.2% of anaplastic thyroid carcinomas. The distribution of PD-L1 positivity was different according to cancer histology types (P < 0.001). All PD-L1-positive cases of follicular thyroid carcinoma and anaplastic thyroid carcinoma showed strong intensity. The proportions of positivity in PD-L1 positive anaplastic thyroid carcinomas were more than 80%. PD-L1 in immune cells was positive in 28.5% of papillary thyroid carcinoma, 9.1% of follicular thyroid carcinomas and 11.1% of anaplastic thyroid carcinomas. There was no significant association between clinicopathologic variables, disease progression, oncogenic mutation and PD-L1 expression. PD-L1 was highly expressed in a subset of patients with advanced thyroid cancer, such as follicular and anaplastic thyroid carcinoma. Identification of PD-L1 expression may have direct therapeutic relevance to patients with refractory thyroid cancer.

Evaluation of E-Cadherin and β-Catenin Immunoreactivity for Determining Undifferentiated Cells in Anaplastic Thyroid Carcinoma

Pathobiology ◽  
2021 ◽  
pp. 1-8
Author(s):  
Risa Kanematsu ◽  
Mitsuyoshi Hirokawa ◽  
Aki Tanaka ◽  
Ayana Suzuki ◽  
Miyoko Higuchi ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Thyroid Carcinoma ◽  
Undifferentiated Carcinoma ◽  
Anaplastic Thyroid Carcinoma ◽  
Carcinoma Cells ◽  
Membrane Expression ◽  
Thyroid Carcinomas ◽  
Nuclear Expression ◽  
Thyroid Transcription Factor 1 ◽  
E Cadherin

<b><i>Introduction:</i></b> An immunohistochemical study has occasionally been performed to diagnose anaplastic thyroid carcinoma (ATC). However, antibodies to confirm the undifferentiated nature of ATC have not yet been evaluated. The aim of this study was to evaluate E-cadherin and β-catenin expressions in immunoreactivity to determine undifferentiated carcinoma cells in the diagnosis of ATC. <b><i>Methods:</i></b> We immunohistochemically examined 29 ATCs, 30 poorly differentiated thyroid carcinomas (PDTCs), 22 well-differentiated thyroid carcinomas (WDTCs), and 3 squamous cell carcinomas. Antibodies for thyroid transcription factor-1 (TTF-1), paired-box gene 8 (PAX8), β-catenin, and E-cadherin were used. <b><i>Results:</i></b> All WDTCs tested positive for TTF-1, PAX8, and E-cadherin. The positive rates of TTF-1, PAX8, and E-cadherin were 93.3, 93.3, and 100%, respectively, in PDTCs and 17.2, 51.7, and 10.3%, respectively, in ATCs. WDTC expressed the lateral cell membrane staining for β-catenin and E-cadherin, whereas PDTC showed circumferential cell membranous expression (fishnet pattern). β-catenin cell membrane expression in ATCs is lost or discontinuous. Carcinoma cells with β-catenin nuclear expression without cell membranous expression were scattered in 72.4% of ATCs but were not observed in the other carcinomas. <b><i>Conclusion:</i></b> We propose 3 immunohistochemical findings to determine undifferentiated carcinoma cells in the diagnosis of ATC: (1) β-catenin nuclear expression with no or reduced cell membranous expression, (2) the loss or discontinuous pattern of E-cadherin expression, and (3) the loss of PAX8 nuclear expression.

scholarly journals Keap1 deletion accelerates mutant K-ras/p53-driven cholangiocarcinoma

2020 ◽  
Vol 318 (3) ◽  
pp. G419-G427 ◽  
Author(s):  
Tatsuhide Nabeshima ◽  
Shin Hamada ◽  
Keiko Taguchi ◽  
Yu Tanaka ◽  
Ryotaro Matsumoto ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cancer Progression ◽  
Stress Responses ◽  
Target Genes ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Related Factor ◽  
Loss Of Function ◽  
P53 Expression ◽  
Nrf2 Activation

The activation of the Kelch-like ECH-associated protein 1 (Keap1)-NF-E2-related factor 2 (Nrf2) pathway contributes to cancer progression in addition to oxidative stress responses. Loss-of-function Keap1 mutations were reported to activate Nrf2, leading to cancer progression. We examined the effects of Keap1 deletion in a cholangiocarcinoma mouse model using a mutant K-ras/ p53 mouse. Introduction of the Keap1 deletion into liver-specific mutant K-ras/ p53 expression resulted in the formation of invasive cholangiocarcinoma. Comprehensive analyses of the gene expression profiles identified broad upregulation of Nrf2-target genes such as Nqo1 and Gstm1 in the Keap1-deleted mutant K-ras/ p53 expressing livers, accompanied by upregulation of cholangiocyte-related genes. Among these genes, the transcriptional factor Sox9 was highly expressed in the dysplastic bile duct. The Keap-Nrf2-Sox9 axis might serve as a novel therapeutic target for cholangiocarcinoma. NEW & NOTEWORTHY The Keap1-Nrf2 system has a wide variety of effects in addition to the oxidative stress response in cancer cells. Addition of the liver-specific Keap1 deletion to mice harboring mutant K-ras and p53 accelerated cholangiocarcinoma formation, together with the hallmarks of Nrf2 activation. This process involved the expansion of Sox9-positive cells, indicating increased differentiation toward the cholangiocyte phenotype.

scholarly journals RET Regulates Human Medullary Thyroid Cancer Cell Proliferation through CDK5 and STAT3 Activation

Biomolecules ◽  
2021 ◽  
Vol 11 (6) ◽  
pp. 860
Author(s):  
Chia-Herng Yue ◽  
Muhammet Oner ◽  
Chih-Yuan Chiu ◽  
Mei-Chih Chen ◽  
Chieh-Lin Teng ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Cancer Cell ◽  
Cancer Progression ◽  
Medullary Thyroid Cancer ◽  
Receptor Protein ◽  
Cancer Cell Proliferation ◽  
Thyroid Cancer Cell ◽  
Cancer Proliferation ◽  
Medullary Thyroid

Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from the parafollicular C-cells, which produces the hormone calcitonin. RET is a transmembrane receptor protein-tyrosine kinase, which is highly expressed in MTC. Our previous studies reported that cyclin-dependent kinase 5 (CDK5) plays a crucial role in cancer progression, including MTC. However, the role of CDK5 in GDNF-induced RET signaling in medullary thyroid cancer proliferation remains unknown. Here, we investigated RET activation and its biochemically interaction with CDK5 in GDNF-induced medullary thyroid cancer proliferation. Our results demonstrated that GDNF stimulated RET phosphorylation and thus subsequently resulted in CDK5 activation by its phosphorylation. Activated CDK5 further caused STAT3 activation by its specific phosphorylation at Ser727. Moreover, we also found that GDNF treatment enhanced ERK1/2 and EGR1 activity, which is involved in p35 activation. Interestingly, we identified for the first time that CDK5 physically interacted with RET protein in MTC. Overall, our results provide a new mechanism for medullary thyroid cancer cell proliferation, suggesting that targeting CDK5 may be a promising therapeutic candidate for human medullary thyroid cancer in the near future.

scholarly journals Enhancer of Zeste Homolog 2 Overexpression Has a Role in the Development of Anaplastic Thyroid Carcinomas

2011 ◽  
Vol 96 (4) ◽  
pp. 1029-1038 ◽  
Author(s):  
Eleonora Borbone ◽  
Giancarlo Troncone ◽  
Angelo Ferraro ◽  
Zuzana Jasencakova ◽  
Lovorka Stojic ◽  
...  
Keyword(s):  
Thyroid Carcinoma ◽  
Anaplastic Thyroid Carcinoma ◽  
Polycomb Group ◽  
Migration And Invasion ◽  
Polycomb Group Protein ◽  
Expression Levels ◽  
Thyroid Carcinomas ◽  
Enhancer Of Zeste ◽  
Pax8 Gene ◽  
Group Protein

Abstract Context: Enhancer of zeste homolog 2 (EZH2) is a histone lysine methyltransferase belonging to the polycomb group protein family. Overexpression of EZH2 has been found in several human malignancies including hematological and solid tumors. Objectives: In this study we investigated the expression levels of EZH2 and its polycomb group protein partners in thyroid carcinoma tissues with different degrees of malignancy to identify potential new therapeutic targets for anaplastic thyroid carcinoma (ATC). Results: We show that high EZH2 expression levels are characteristic of undifferentiated ATC, whereas no significant changes were observed in well-differentiated papillary and follicular thyroid carcinomas as compared with normal thyroid. Knockdown of EZH2 in ATC cell lines results in cell growth inhibition, loss of anchorage-independent growth, migration, and invasion properties. Moreover, we demonstrate that EZH2 directly controls differentiation of ATC cells by silencing the thyroid specific transcription factor paired-box gene 8 (PAX8). Conclusions: EZH2 is specifically overexpressed in ATC, and it directly contributes to transcriptional silencing of PAX8 gene and ATC differentiation.

scholarly journals Involvement of STAT5 in Oncogenesis

Biomedicines ◽  
2020 ◽  
Vol 8 (9) ◽  
pp. 316
Author(s):  
Clarissa Esmeralda Halim ◽  
Shuo Deng ◽  
Mei Shan Ong ◽  
Celestial T. Yap
Keyword(s):  
Cell Proliferation ◽  
Cancer Progression ◽  
Transcriptional Activity ◽  
Target Genes ◽  
Kinase Inhibitors ◽  
Cyclin D ◽  
Signal Transducer ◽  
Stat Proteins ◽  
Constitutive Activation ◽  
Target Molecules

Signal transducer and activator of transcription (STAT) proteins, and in particular STAT3, have been established as heavily implicated in cancer. Recently, the involvement of STAT5 signalling in the pathology of cancer has been shown to be of increasing importance. STAT5 plays a crucial role in the development of the mammary gland and the homeostasis of the immune system. However, in various cancers, aberrant STAT5 signalling promotes the expression of target genes, such as cyclin D, Bcl-2 and MMP-2, that result in increased cell proliferation, survival and metastasis. To target constitutive STAT5 signalling in cancers, there are several STAT5 inhibitors that can prevent STAT5 phosphorylation, dimerisation, or its transcriptional activity. Tyrosine kinase inhibitors (TKIs) that target molecules upstream of STAT5 could also be utilised. Consequently, since STAT5 contributes to tumour aggressiveness and cancer progression, inhibiting STAT5 constitutive activation in cancers that rely on its signalling makes for a promising targeted treatment option.

scholarly journals Hif-1α Inhibitors Could Successfully Inhibit the Progression of Differentiated Thyroid Cancer in Vitro

2020 ◽  
Vol 13 (9) ◽  
pp. 208
Author(s):  
Min-Hee Kim ◽  
Tae Hyeong Lee ◽  
Jin Soo Lee ◽  
Dong-Jun Lim ◽  
Peter Chang-Whan Lee
Keyword(s):  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Progression ◽  
Hypoxia Inducible Factor ◽  
Soft Agar ◽  
Dependent Manner ◽  
Thyroid Cancer Cell Lines ◽  
Dose Dependent

Hypoxia-inducible factor (HIF)-1α plays an important role in cancer progression. In various cancers, including thyroid cancer, overexpression of HIF-1α is related to poor prognosis or treatment response. However, few studies have investigated the role of HIF-1α inhibition in thyroid cancer progression. We evaluated the utility of the HIF-1α inhibitor IDF-11774 in vitro utilizing two thyroid cancer cell lines, K1 and BCPAP. Both cell lines were tested to elucidate the effects of IDF-11774 on cell proliferation and migration using soft agar and invasion assays. Here, we found that a reduction of HIF-1α expression in BCPAP cells was observed after treatment with IDF-11774 in a dose-dependent manner. Moreover, cell proliferation, migration, and anchorage-independent growth were effectively inhibited by IDF-11774 in BCPAP cells but not in K1 cells. Additionally, invasion of BCPAP but not K1 cells was controlled with IDF-11774 in a dose-dependent manner. Our findings suggest that promoting the degradation of HIF-1α could be a strategy to manage progression and that HIF-1α inhibitors are potent drugs for thyroid cancer treatment.

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