scholarly journals Dual Oncogenic/Anti-Oncogenic Role of PATZ1 in FRTL5 Rat Thyroid Cells Transformed by the Ha-RasV12 Oncogene

Genes ◽  
2019 ◽  
Vol 10 (2) ◽  
pp. 127 ◽  
Author(s):  
Michela Vitiello ◽  
Giuseppe Palma ◽  
Mario Monaco ◽  
Anna Bello ◽  
Simona Camorani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Thyroid Cancer ◽  
Cancer Cells ◽  
Tumor Growth Rate ◽  
Stem Cell Markers ◽  
Thyroid Cells ◽  
Mesenchymal Transition ◽  
Rat Thyroid ◽  
The Impact ◽  
Thyroid Cancer Cells

PATZ1 is a transcriptional factor downregulated in thyroid cancer whose re-expression in thyroid cancer cells leads to a partial reversion of the malignant phenotype, including the capacity to proliferate, migrate, and undergo epithelial-to-mesenchymal transition. We have recently shown that PATZ1 is specifically downregulated downstream of the Ras oncogenic signaling through miR-29b, and that restoration of PATZ1 in Ha-Ras transformed FRTL5 rat thyroid cells is able to inhibit their capacities to proliferate and migrate in vitro. Here, we analyzed the impact of PATZ1 expression on the in vivo tumorigenesis of these cells. Surprisingly, FRTL5-Ras-PATZ1 cells showed enhanced tumor initiation when engrafted in nude mice, even if their tumor growth rate was reduced compared to that of FRTL5-Ras control cells. To further investigate the cause of the enhanced tumor engraftment of FRTL5-Ras-PATZ1 cells, we analyzed the stem-like potential of these cells through their capacity to grow as thyrospheres. The results showed that restoration of PATZ1 expression in these cells increases stem cell markers’ expression and self-renewal ability of the thyrospheres while limiting their growth capacity. Therefore, we suggest that PATZ1 may play a role in enhancing the stem cell potential of thyroid cancer cells, but, at the same time, it impairs the proliferation of non-stem cells.

scholarly journals Phosphoinositide-3-kinase inhibition induces sodium/iodide symporter expression in rat thyroid cells and human papillary thyroid cancer cells

2008 ◽  
Vol 199 (2) ◽  
pp. 243-252 ◽  
Author(s):  
Takahiko Kogai ◽  
Saima Sajid-Crockett ◽  
Lynell S Newmarch ◽  
Yan-Yun Liu ◽  
Gregory A Brent
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Papillary Thyroid Cancer ◽  
Pi3k Pathway ◽  
Papillary Thyroid ◽  
Iodide Uptake ◽  
Thyroid Cells ◽  
Pathway Inhibition ◽  
Rat Thyroid ◽  
Thyroid Cancer Cells

TSH stimulation of sodium iodide symporter (NIS) expression in thyroid cancer promotes radioiodine uptake and is required to deliver an effective treatment dose. Activation of the insulin/phosphoinositide-3-kinase (PI3K) signaling pathway in TSH-stimulated thyroid cells reduces NIS expression at the transcriptional level. We, therefore, investigated the effects of PI3K pathway inhibition on iodide uptake and NIS expression in rat thyroid cell lines and human papillary thyroid cancer cells. A PI3K inhibitor, LY294002, significantly enhanced iodide uptake in two rat thyroid cell lines, FRTL-5 and PCCL3. The induction of Nis mRNA by LY294002 occurred 6 h after treatment, and was abolished by a translation inhibitor, cycloheximide. Expression of the transcription factor, Pax8, which stimulates NIS expression, was significantly increased in PCCL3 cells after LY294002 treatment. Removal of insulin abrogated the stimulatory effects of LY294002 on NIS mRNA and protein expression, but not on iodide uptake. These findings suggest that PI3K pathway inhibition results in post-translational stimulation of NIS. Inhibition of the PI3K pathway also significantly increased iodide uptake (∼3.5-fold) in BHP 2–7 papillary thyroid cancer cells (Ret/PTC1 positive), engineered to constitutively express NIS. Pharmacological inhibition of Akt, a factor stimulated by the PI3K pathway, increased exogenous NIS expression in BHP 2–7 as was seen with LY294002, but not increase the endogenous NIS expression in FRTL-5 cells. PI3K pathway inhibition increases functional NIS expression in rat thyroid cells and some papillary thyroid cancer cells by several mechanisms. PI3K inhibitors have the potential to increase radioiodide accumulation in some differentiated thyroid cancer.

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

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.

scholarly journals Synergistic Antitumor Effect of BKM120 with Prima-1Met Via Inhibiting PI3K/AKT/mTOR and CPSF4/hTERT Signaling and Reactivating Mutant P53

2018 ◽  
Vol 45 (5) ◽  
pp. 1772-1786 ◽  
Author(s):  
Zongjuan Li ◽  
Xiangdong Xu ◽  
Yizhuo Li ◽  
Kun Zou ◽  
Zhuo Zhang ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Colony Formation ◽  
Antitumor Effect ◽  
Migration And Invasion ◽  
Mutant P53 ◽  
Stem Cell Markers ◽  
Combinational Treatment ◽  
Thyroid Cancer Cells

Background/Aims: PI3KCA and mutant p53 are associated with tumorigenesis and the development of cancers. NVP-BKM120, a selective pan-PI3K inhibitor, exerts the antitumor activity by suppressing the PI3K signaling pathway. Prima-1Met, a low molecular weight compound, can rescue the gain-of-function of mutant p53 by restoring its transcriptional function. In this study, we investigated whether PI3K inhibition combined with mutant p53 reactivation could enhance the antitumor effect in thyroid cancer cells. Methods: The effects of BKM120 and Prima-1Met on the proliferation, apoptosis, migration and invasion of thyroid cancer cells were measured by MTT, colony formation, flow cytometry, wound-healing and transwell assays, respectively. Thyroid differentiation was assessed by detecting the expression levels of specific markers using RT-PCR and Western blot. The in vivo antitumor efficacy was analyzed in a mouse xenograft model. Results: The combinational treatment of BKM120 and Prima-1Met significantly enhanced the inhibitions of cell viability, colony formation, migration and invasion, and the induction of apoptosis in thyroid cell lines, and synergistically suppressed tumor xenograft growth by inhibiting the PI3K/Akt/mTOR and EMT signaling pathways, up-regulating p53 targeted genes, and triggering the release of cytochrome c. Moreover, the combination of BKM120 and Prima-1Met suppressed the stemlike traits of thyroid cancer cells and promoted their differentiation by upregulating the expression of thyroid-specific differentiation markers and repressing the expression of cancer stem cell markers. Furthermore, the mechanism study demonstrated that the combinational treatment synergistically abrogated the binding of CPSF4 at the promoter of hTERT and thus suppressed hTERT expression. Consistently, overexpression of hTERT rescued the inhibitions of cell viability, invasion and stem-like traits mediated by the combination of BKM120 and Prima-1Met. Conclusion: Our results showed that the combination of BKM120 with Prima-1Met synergistically suppressed the growth of thyroid cancer cells and tumor xenografts via inhibiting PI3K/Akt/mTOR and CPSF4/hTERT signaling and reactivating mutant p53.

scholarly journals Targeting XPO1 and PAK4 in 8505C Anaplastic Thyroid Cancer Cells: Putative Implications for Overcoming Lenvatinib Therapy Resistance

2019 ◽  
Vol 21 (1) ◽  
pp. 237 ◽  
Author(s):  
Husain Yar Khan ◽  
James Ge ◽  
Misako Nagasaka ◽  
Amro Aboukameel ◽  
Gabriel Mpilla ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Rho Gtpase ◽  
Kinase Inhibitor ◽  
Progression Free Survival ◽  
Anaplastic Thyroid Cancer ◽  
Therapy Resistance ◽  
Molecular Profile ◽  
The Impact ◽  
Thyroid Cancer Cells

Lenvatinib is a multitargeted tyrosine kinase inhibitor (TKI) that shows improved median progression-free survival (PFS) in patients with thyroid carcinomas. However, virtually all patients ultimately progress, indicating the need for a better understanding of the mechanisms of resistance. Here, we examined the molecular profile of anaplastic thyroid cancer cells (8505C) exposed to lenvatinib and found that long-term exposure to lenvatinib caused phenotypic changes. Consistent with change toward mesenchymal morphology, activation of pro-survival signaling, nuclear exporter protein exportin 1 (XPO1) and Rho GTPase effector p21 activated kinases (PAK) was also observed. RNA-seq analysis showed that prolonged lenvatinib treatment caused alterations in numerous cellular pathways and several oncogenes such as CEACAM (carcinoembryonic antigen-related cell adhesion molecule) and NUPR1 (Nuclear protein 1) were also upregulated. Further, we evaluated the impact of XPO1 and PAK4 inhibition in the presence or absence of lenvatinib. Targeted inhibition of XPO1 and PAK4 could sensitize the 8505C cells to lenvatinib. Both XPO1 and PAK4 inhibitors, when combined with lenvatinib, showed superior anti-tumor activity in 8505C sub-cutaneous xenograft. These studies bring forward novel drug combinations to complement lenvatinib for treating anaplastic thyroid cancer. Such combinations may possibly reduce the chances of lenvatinib resistance in thyroid cancer patients.

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

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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