15-Deoxy-Δ12,14-prostaglandin J2 inhibits migration of human thyroid carcinoma cells by disrupting focal adhesion complex and adherens junction

The invasive behavior of glioblastoma is essential to its aggressive potential. Here, we show that pleckstrin homology domain interacting protein (PHIP), acting through effects on the force transduction layer of the focal adhesion complex, drives glioblastoma motility and invasion. Immunofluorescence analysis localized PHIP to the leading edge of glioblastoma cells, together with several focal adhesion proteins: vinculin (VCL), talin 1 (TLN1), integrin beta 1 (ITGB1), as well as phosphorylated forms of paxillin (pPXN) and focal adhesion kinase (pFAK). Confocal microscopy specifically localized PHIP to the force transduction layer, together with TLN1 and VCL. Immunoprecipitation revealed a physical interaction between PHIP and VCL. Targeted suppression of PHIP resulted in significant down-regulation of these focal adhesion proteins, along with zyxin (ZYX), and produced profoundly disorganized stress fibers. Live-cell imaging of glioblastoma cells overexpressing a ZYX-GFP construct demonstrated a role for PHIP in regulating focal adhesion dynamics. PHIP silencing significantly suppressed the migratory and invasive capacity of glioblastoma cells, partially restored following TLN1 or ZYX cDNA overexpression. PHIP knockdown produced substantial suppression of tumor growth upon intracranial implantation, as well as significantly reduced microvessel density and secreted VEGF levels. PHIP copy number was elevated in the classical glioblastoma subtype and correlated with elevated EGFR levels. These results demonstrate PHIP’s role in regulating the actin cytoskeleton, focal adhesion dynamics, and tumor cell motility, and identify PHIP as a key driver of glioblastoma migration and invasion.

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Regulation of HLA-DR and Costimulatory B7 Molecules in Human Thyroid Carcinoma Cells: Differential Binding of Transcription Factors to the HLA-DRα Promoter

Thyroid ◽

10.1089/thy.1998.8.361 ◽

1998 ◽

Vol 8 (5) ◽

pp. 361-369 ◽

Cited By ~ 9

Author(s):

NITZA LAHAT ◽

MICHAL A. RAHAT ◽

ORIT SADEH ◽

AMALIA KINARTY ◽

ZAKI KRAIEM

Keyword(s):

Transcription Factors ◽

Thyroid Carcinoma ◽

Carcinoma Cells ◽

Human Thyroid ◽

Hla Dr ◽

B7 Molecules ◽

Differential Binding

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Coexpression of Functionally Active Receptors for Thyrotropin and Platelet-Derived Growth Factor in Human Thyroid Carcinoma Cells*

Endocrinology ◽

10.1210/endo-129-4-2187 ◽

1991 ◽

Vol 129 (4) ◽

pp. 2187-2193 ◽

Cited By ~ 47

Author(s):

NILS-ERIK HELDIN ◽

DUBRAVKA CVEJIĆ ◽

STAFFAN SMEDS ◽

BENGT WESTERMARK

Keyword(s):

Growth Factor ◽

Thyroid Carcinoma ◽

Carcinoma Cells ◽

Platelet Derived Growth Factor ◽

Human Thyroid

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Differential roles of RET isoforms in medullary and papillary thyroid carcinomas

Endocrine Related Cancer ◽

10.1530/erc-16-0393 ◽

2017 ◽

Vol 24 (1) ◽

pp. 53-69 ◽

Cited By ~ 20

Author(s):

Eric Y Lian ◽

Sarah M Maritan ◽

Jessica G Cockburn ◽

Katayoon Kasaian ◽

Mathieu J F Crupi ◽

...

Keyword(s):

Thyroid Carcinoma ◽

Cell Survival ◽

Tumour Progression ◽

Carcinoma Cells ◽

Protein Isoforms ◽

Human Thyroid ◽

Papillary Thyroid ◽

Anoikis Resistance ◽

Thyroid Carcinomas ◽

And Migration

The RET receptor tyrosine kinase mediates cell proliferation, survival and migration in embryogenesis and is implicated in the transformation and tumour progression in multiple cancers. RET is frequently mutated and constitutively activated in familial and sporadic thyroid carcinomas. As a result of alternative splicing, RET is expressed as two protein isoforms, RET9 and RET51, which differ in their unique C-terminal amino acids. These isoforms have distinct intracellular trafficking and associated signalling complexes, but functional differences are not well defined. We used shRNA-mediated knockdown (KD) of individual RET isoforms or of total RET to evaluate their functional contributions in thyroid carcinoma cells. We showed that RET is required for cell survival in medullary (MTC) but not papillary thyroid carcinoma (PTC) cells. In PTC cells, RET depletion reduced cell migration and induced a flattened epithelial-like morphology. RET KD decreased the expression of mesenchymal markers and matrix metalloproteinases and reduced anoikis resistance and invasive potential. Further, we showed that RET51 depletion had significantly greater effects on each of these processes than RET9 depletion in both MTC and PTC cells. Finally, we showed that expression of RET, particularly RET51, was correlated with malignancy in a panel of human thyroid tumour tissues. Together, our data show that RET expression promotes a more mesenchymal phenotype with reduced cell–cell adhesion and increased invasiveness in PTC cell models, but is more important for tumour cell survival, proliferation and anoikis resistance in MTC models. Our data suggest that the RET51 isoform plays a more prominent role in mediating these processes compared to RET9.

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Ligands for Peroxisome Proliferator-Activated Receptor γ Inhibit Growth and Induce Apoptosis of Human Papillary Thyroid Carcinoma Cells

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.5.7493 ◽

2001 ◽

Vol 86 (5) ◽

pp. 2170-2177 ◽

Cited By ~ 4

Author(s):

Kazuyasu Ohta ◽

Toyoshi Endo ◽

Kazutaka Haraguchi ◽

Jerome M. Hershman ◽

Toshimasa Onaya

Keyword(s):

Papillary Thyroid Carcinoma ◽

Thyroid Carcinoma ◽

Cell Lines ◽

Carcinoma Cell ◽

Carcinoma Cells ◽

Human Thyroid ◽

Peroxisome Proliferator ◽

Papillary Thyroid ◽

Peroxisome Proliferator Activated Receptor ◽

Carcinoma Cell Lines

Ligands for peroxisome proliferator-activated receptor γ (PPARγ) induce apoptosis and exert antiproliferative effects on several carcinoma cell lines. The present study investigates the expression of PPARγ and the possibility that agonists for PPARγ also inhibit the growth of human thyroid carcinoma cells. We examined this hypothesis using six cell lines, designated BHP thyroid carcinoma cells, which originated from patients with papillary thyroid carcinoma. RT-PCR analysis revealed that the thyroid carcinoma cell lines BHP2–7, 7–13, 10–3, and 18–21 express PPARγ. More PPARγ was expressed in carcinoma than in adjacent normal thyroid tissue in three of six samples of human papillary carcinoma of the thyroid. PPARγ-positive thyroid carcinoma cells were treated with agonists of PPARγ, troglitazone, BRL 49653, and 15-deoxy-Δ12,14-prostaglandin J2. Troglitazone (10μ mol/L), BRL 49653 (10 μmol/L), and 15-deoxy-Δ12,14-prostaglandin J2 (1 μg/mL) decreased[ 3H]thymidine incorporation and reduced cell number, respectively, in BHP carcinoma cell lines that expressed PPARγ. Under low serum conditions, ligands for PPARγ induced condensation of the nucleus and fragmentation of chromatin into nucleosome ladders. These findings indicate that the death of thyroid carcinoma cells is a form of apoptosis. To investigate the molecular mechanism of the apoptosis, we assessed expression of the apoptosis-regulatory genes bcl-2, bax, and c-myc. Troglitazone significantly increased the expression of c-myc messenger RNA but had no effect on the expression of bcl-2 and bax in thyroid carcinoma cells. These results suggest that, at least in part, the induction of apoptosis in human papillary thyroid carcinoma cells may be due to an increase of c-myc. Troglitazone (500 mg/kg·day) significantly inhibited tumor growth and prevented distant metastasis of BHP18–21 tumors in nude mice in vivo. Taken together, these results suggest that PPARγ agonist inhibit cell growth of some types of human thyroid cancer.

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