scholarly journals DDR1 regulates thyroid cancer cell differentiation via IGF-2/IR-A autocrine signaling loop

2019 ◽  
Vol 26 (1) ◽  
pp. 197-214 ◽  
Author(s):  
Veronica Vella ◽  
Maria Luisa Nicolosi ◽  
Patrizia Cantafio ◽  
Michele Massimino ◽  
Rosamaria Lappano ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Differentiation ◽  
Epithelial To Mesenchymal Transition ◽  
Human Thyroid ◽  
Autocrine Signaling ◽  
Differentiation Markers ◽  
Autocrine Loop ◽  
Mesenchymal Transition ◽  
Poorly Differentiated ◽  
Induced Changes

Patients with thyroid cancers refractory to radioiodine (RAI) treatment show a limited response to various therapeutic options and a low survival rate. The recent use of multikinase inhibitors has also met limited success. An alternative approach relies on drugs that induce cell differentiation, as the ensuing increased expression of the cotransporter for sodium and iodine (NIS) may partially restore sensitivity to radioiodine. The inhibition of the ERK1/2 pathway has shown some efficacy in this context. Aggressive thyroid tumors overexpress the isoform-A of the insulin receptor (IR-A) and its ligand IGF-2; this IGF-2/IR-A loop is associated with de-differentiation and stem-like phenotype, resembling RAI-refractory tumors. Importantly, IR-A has been shown to be positively modulated by the non-integrin collagen receptor DDR1 in human breast cancer. Using undifferentiated human thyroid cancer cells, we now evaluated the effects of DDR1 on IGF-2/IR-A loop and on markers of cell differentiation and stemness. DDR1 silencing or downregulation caused significant reduction of IR-A and IGF-2 expression, and concomitant increased levels of differentiation markers (NIS, Tg, TSH, TPO). Conversely, markers of epithelial-to-mesenchymal transition (Vimentin, Snail-2, Zeb1, Zeb2 and N-Cadherin) and stemness (OCT-4, SOX-2, ABCG2 and Nanog) decreased. These effects were collagen independent. In contrast, overexpression of either DDR1 or its kinase-inactive variant K618A DDR1-induced changes suggestive of less differentiated and stem-like phenotype. Collagen stimulation was uneffective. In conclusion, in poorly differentiated thyroid cancer, DDR1 silencing or downregulation blocks the IGF-2/IR-A autocrine loop and induces cellular differentiation. These results may open novel therapeutic approaches for thyroid cancer.

scholarly journals Notch Signaling Is Involved in Expression of Thyrocyte Differentiation Markers and Is Down-Regulated in Thyroid Tumors

2008 ◽  
Vol 93 (10) ◽  
pp. 4080-4087 ◽  
Author(s):  
E. Ferretti ◽  
E. Tosi ◽  
A. Po ◽  
A. Scipioni ◽  
R. Morisi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Thyroid Cancer ◽  
Notch Signaling ◽  
Notch Pathway ◽  
Human Thyroid ◽  
Thyroid Tumors ◽  
Follicular Cells ◽  
Differentiation Markers ◽  
Thyroid Follicular Cells ◽  
Thyroid Cancer Cells

Context: Notch genes encode receptors for a signaling pathway that regulates cell growth and differentiation in various contexts, but the role of Notch signaling in thyroid follicular cells has never been fully published. Objective: The objective of the study was to characterize the expression of Notch pathway components in thyroid follicular cells and Notch signaling activities in normal and transformed thyrocytes. Design/Setting and Patients: Expression of Notch pathway components and key markers of thyrocyte differentiation was analyzed in murine and human thyroid tissues (normal and tumoral) by quantitative RT-PCR and immunohistochemistry. The effects of Notch overexpression in human thyroid cancer cells and FTRL-5 cells were explored with analysis of gene expression, proliferation assays, and experiments involving transfection of a luciferase reporter construct containing human NIS promoter regions. Results: Notch receptors are expressed during the development of murine thyrocytes, and their expression levels parallel those of thyroid differentiation markers. Notch signaling characterized also normal adult thyrocytes and is regulated by TSH. Notch pathway components are variably expressed in human normal thyroid tissue and thyroid tumors, but expression levels are clearly reduced in undifferentiated tumors. Overexpression of Notch-1 in thyroid cancer cells restores differentiation, reduces cell growth rates, and stimulates NIS expression via a direct action on the NIS promoter. Conclusion: Notch signaling is involved in the determination of thyroid cell fate and is a direct regulator of thyroid-specific gene expression. Its deregulation may contribute to the loss of differentiation associated with thyroid tumorigenesis.

scholarly journals Mining Prognostic Significance Genes in Human Thyroid Cancer Using Bioinformatics Analysis

2021 ◽  
Author(s):  
Hui Zhao ◽  
Pengjie Li ◽  
Junjian Li ◽  
Lian Duan ◽  
Yanzhu Jiao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Extracellular Matrix ◽  
Thyroid Cancer ◽  
Function Analysis ◽  
Akt Signaling ◽  
Differentially Expressed ◽  
Human Thyroid ◽  
Marker Genes ◽  
Clinical Prognosis ◽  
Mesenchymal Transition

Abstract Background Thyroid carcinoma (THC) is very common, yet its pathogenesis and the key tumor marker genes remain unclear.Methods Gene expression datasets from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas Project (TCGA) were used for gene differential expression analysis. Functional annotation analysis, Clinical prognosis analysis and Differential DNA methylation analysis were conducted on the differentially expressed genes (DEGs). Results Compared with induced pluripotent stem cells (iPSCs), 237 differentially expressed THC intersection genes derived from GEO and TCGA were obtained, of which 153 genes were closely related to clinicopathological features and prognostic effects. Biological function analysis indicated that most of these DEGs were involved in the proteinaceous extracellular matrix, epithelial-to-mesenchymal transition (EMT), and PI3K-Akt signaling pathway, resulting in effects on tumor invasion and metastasis. Finally, the results of differential methylation levels demonstrated that the high expression of 4 genes (CHI3L1, NFE2L3, S100A2, and LAMB3) was strongly correlated with the development of thyroid cancer.Conclusions Proteinaceous extracellular matrix, EMT, and PI3K-Akt signaling pathways were of great significance in the metastasis and invasion of THC. Genes such as CHI3L1, NFE2L3, S100A2, and LAMB3 were susceptible to THC.

scholarly journals A Bioinformatic Pipeline Places STAT5A as a miR-650 Target in Poorly Differentiated Aggressive Breast Cancer

2020 ◽  
Vol 21 (20) ◽  
pp. 7720
Author(s):  
Eric López-Huerta ◽  
Ezequiel M. Fuentes-Pananá
Keyword(s):  
Breast Cancer ◽  
Target Gene ◽  
Epithelial To Mesenchymal Transition ◽  
Differential Expression Analysis ◽  
Target Prediction ◽  
Suppressor Gene ◽  
Gene Target ◽  
Mesenchymal Transition ◽  
Genomic Aberrations ◽  
Poorly Differentiated

Breast cancer (BRCA) is a leading cause of mortality among women. Tumors often acquire aggressive features through genomic aberrations affecting cellular programs, e.g., the epithelial to mesenchymal transition (EMT). EMT facilitates metastasis leading to poor prognosis. We previously observed a correlation between an amplification of miR-650 (Amp-650) and EMT features in BRCA samples isolated from Mexican patients. In this study, we explored the cBioportal database aiming to extend that observation and better understand the importance of Amp-650 for BRCA aggressiveness. We found that Amp-650 is more frequent in aggressive molecular subtypes of BRCA, as well as in high grade poorly differentiated tumors, which we confirmed in an external miRNA expression database. We performed differential expression analysis on samples harboring Amp-650, taking advantage of gene target prediction tools and tumor suppressor gene databases to mine several hundreds of differentially underexpressed genes. We observed STAT5A as a likely putative target gene for miR-650 in aggressive poorly differentiated BRCA. Samples with both Amp-650 and low expression of STAT5A had less overall survival than samples with either or none of the alterations. No target gene has been described for miR-650 in BRCA, thus, this bioinformatic study provides valuable information that should be corroborated experimentally.

scholarly journals FOXE1 regulates migration and invasion in thyroid cancer cells and targets ZEB1

2020 ◽  
Vol 27 (3) ◽  
pp. 137-151 ◽  
Author(s):  
Jesús Morillo-Bernal ◽  
Lara P Fernández ◽  
Pilar Santisteban
Keyword(s):  
Cell Migration ◽  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Susceptibility ◽  
Human Thyroid ◽  
Migration And Invasion ◽  
Migration Ability ◽  
Mesenchymal Transition ◽  
Thyroid Cancer Cells

FOXE1 is a thyroid-specific transcription factor essential for thyroid gland development and maintenance of the differentiated state. Interestingly, a strong association has been recently described between FOXE1 expression and susceptibility to thyroid cancer, but little is known about the mechanisms underlying FOXE1-induced thyroid tumorigenesis. Here, we used a panel of human thyroid cancer-derived cell lines covering the spectrum of thyroid cancer phenotypes to examine FOXE1 expression and to test for correlations between FOXE1 expression, the allele frequency of two SNPs and a length polymorphism in or near the FOXE1 locus associated with cancer susceptibility, and the migration ability of thyroid cancer cell lines. Results showed that FOXE1 expression correlated with differentiation status according to histological sub-type, but not with SNP genotype or cell migration ability. However, loss-and-gain-of-function experiments revealed that FOXE1 modulates cell migration, suggesting a role in epithelial-to-mesenchymal transition (EMT). Our previous genome-wide expression analysis identified Zeb1, a major EMT inducer, as a putative Foxe1 target gene. Indeed, gene silencing of FOXE1 decreased ZEB1 expression, whereas its overexpression increased ZEB1 transcriptional activity. FOXE1 was found to directly interact with the ZEB1 promoter. Lastly, ZEB1 silencing decreased the ability of thyroid tumoral cells to migrate and invade, pointing to its importance in thyroid tumor mestastases. In conclusion, we have identified ZEB1 as a bona fide target of FOXE1 in thyroid cancer cells, which provides new insights into the role of FOXE1 in regulating cell migration and invasion in thyroid cancer.

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