scholarly journals Smad Ubiquitination Regulatory Factor 1 (Smurf1) Promotes Thyroid Cancer Cell Proliferation and Migration via Ubiquitin-Dependent Degradation of Kisspeptin-1

2018 ◽  
Vol 49 (5) ◽  
pp. 2047-2059 ◽  
Author(s):  
Chunyan Yan ◽  
Haiying Su ◽  
Xiyuan Song ◽  
Huiling Cao ◽  
Lingling Kong ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Thyroid Tumor ◽  
Thyroid Cancer Cell ◽  
Cancer Proliferation ◽  
Proliferation And Apoptosis ◽  
Proliferation And Metastasis ◽  
Thyroid Cancer Cells

Background/Aims: Thyroid cancer is the most common malignancy in human endocrine system. Smad ubiquitination regulatory factor 1 (Smurf1) is an E3 ubiquitin-protein ligase in ubiquitin-proteasome pathway (UPP) system. This study aimed to investigate the effects of Smurf1 on thyroid cancer proliferation and metastasis, as well as underlying potential mechanism. Methods: The expression levels of Smurf1 in thyroid tumor tissues and thyroid cancer cells were detected by western blotting and qRT-PCR. Then, the effects of up-regulation or down-regulation of Smurf1 on thyroid cancer cell viability, migration, invasion, proliferation and apoptosis were measured using trypan blue exclusion assay, two-chamber migration (invasion) assay, cell colony formation assay and Guava Nexin assay, respectively. The ubiquitination of kisspeptin-1 (KISS-1) was assessed by protein ubiquitination assay. Finally, the effects of KISS-1 overexpression on activity of nuclear factor-kappa B (NF-κB) signaling pathway, as well as thyroid cancer cell viability, migration, invasion, proliferation and apoptosis were also detected, respectively. Results: Smurf1 was highly expressed in thyroid tumor tissues and thyroid cancer cells. Up-regulation of Smurf1 promoted the viability, migration, invasion and proliferation of thyroid cancer cells. Knockdown of Smurf1 had opposite effects. Moreover, smurf1 promoted the ubiquitination of KISS-1. Overexpression of KISS-1 inactivated NF-κB pathway, suppressed thyroid cancer cell viability, migration, invasion and proliferation, and induced cell apoptosis. Conclusion: Up-regulation of Smurf1 exerted important roles in thyroid cancer formation and development by promoting thyroid cancer proliferation and metastasis. The ubiquitin-dependent degradation of KISS-1 induced by Smurf1 and the activation of NF-κB signaling pathway might be involved in this process. Smurf1 could be an effective therapy target and biomarker for thyroid cancer treatment.

scholarly journals Chlorotoxin Conjugated with Saporin Reduces Viability of ML-1 Thyroid Cancer Cells In Vitro

2019 ◽  
Author(s):  
Husref Rizvanovic ◽  
A Daniel Pinheiro ◽  
Kyoungtae Kim ◽  
Johnson Thomas
Keyword(s):  
Thyroid Cancer ◽  
Cell Viability ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Unmet Need ◽  
Matrix Metalloproteinase 2 ◽  
Dependent Manner ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cells

AbstractBackgroundAlthough differentiated thyroid cancer has good prognosis, radioactive iodine (RAI) resistant thyroid cancer is difficult to treat. Current therapies for progressive RAI resistant thyroid cancer are not very effective. There is an unmet need for better therapeutic agents in this scenario. Studies have shown that aggressive thyroid cancers express matrix metalloproteinase −2 (MMP-2). Chlorotoxin is a selective MMP-2 agonist. Given that Saporin is a well-known ribosome-inactivating protein used for anti-cancer treatment, we hypothesized that Chlorotoxin-conjugated Saporin (CTX-SAP) would inhibit the growth of aggressive thyroid cancer cell lines expressing MMP-2.MethodsThe ML-1 thyroid cancer cell line was used for this study because it is known to express MMP-2. ML-1 cells were treated with a toxin consisting of biotinylated Chlorotoxin bonded with a secondary conjugate of Streptavidin-ZAP containing Saporin (CTX-SAP) from 0 to 600 nM for 72 hours. Then, cell viability was measured via XTT assay at an absorbance of A450-630. Control experiments were set up using Chlorotoxin and Saporin individually at the same varying concentrations.ResultsAfter 7 hours of incubation, there was a statistically significant reduction in cell viability with increasing concentrations of the CTX-SAP conjugate (F=4.286, p=0.0057). In particular, the cell viability of ML-1 cells was decreased by 49.77% with the treatment of 600 nM of CTX-SAP (F=44.24), and the reduction in cell viability was statistically significant (Dunnett’s test p<0.0001). In contrast, individual Chlorotoxin or Saporin in increasing concentrations had no significant effect on cell viability using similar assay.ConclusionThis in vitro study demonstrated the efficacy of a CTX-SAP conjugate in reducing the viability of ML-1 thyroid cancer cells in a dose dependent manner. Further studies are needed to delineate the effectiveness of CTX-SAP in the treatment of aggressive thyroid cancer. Our study points towards MMP-2 as a potential target for RAI-resistant thyroid cancer.

scholarly journals Interplay between thyroid cancer cells and macrophages: effects on IL-32 mediated cell death and thyroid cancer cell migration

2019 ◽  
Vol 42 (5) ◽  
pp. 691-703 ◽  
Author(s):  
Yvette J. E. Sloot ◽  
Katrin Rabold ◽  
Thomas Ulas ◽  
Dennis M. De Graaf ◽  
Bas Heinhuis ◽  
...  
Keyword(s):  
Cell Death ◽  
Cell Migration ◽  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Cancer Cell Migration ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cells

scholarly journals Induction of apoptosis and necrosis by zinc in human thyroid cancer cell lines

2001 ◽  
Vol 169 (2) ◽  
pp. 417-424 ◽  
Author(s):  
M Iitaka ◽  
S Kakinuma ◽  
S Fujimaki ◽  
I Oosuga ◽  
T Fujita ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Cancer Cell Lines ◽  
Human Thyroid ◽  
Dependent Manner ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cell Lines ◽  
Thyroid Cancer Cells

Zinc at concentrations of 150, microM or higher induced necrosis as well as apoptosis in thyroid cancer cell lines. Necrosis was induced by zinc in a dose-dependent manner, whereas apoptosis did not increase at higher concentrations of zinc. The expression of the antiapoptotic protein phosphorylated Bad was markedly increased, whereas the expression of the proapoptotic proteins Bax and Bad decreased following Zn(2+) exposure. Zn(2+) induced rapid degradation of IkappaB, and an increase in the binding of nuclear transcription factor-kappaB (NF-kappaB). These observations indicate that antiapoptotic pathways were activated in thyroid cancer cells following exposure to Zn(2+). This may be a self-defence mechanism against apoptosis and may underlie the general resistance of thyroid cancer cells to apoptotic stimuli. Zinc may be a potential cytotoxic agent for the treatment of thyroid cancer.

scholarly journals Selumetinib Activity in Thyroid Cancer Cells: Modulation of Sodium Iodide Symporter and Associated miRNAs

2018 ◽  
Vol 19 (7) ◽  
pp. 2077 ◽  
Author(s):  
Sabine Wächter ◽  
Annette Wunderlich ◽  
Brandon Greene ◽  
Silvia Roth ◽  
Moritz Elxnat ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Sodium Iodide ◽  
Thyroid Cancer Cell ◽  
Sodium Iodide Symporter ◽  
Radioiodine Uptake ◽  
Thyroid Cancer Cell Lines ◽  
Thyroid Cancer Cells

Background: The MEK (mitogen-activated protein kinase)–inhibitor selumetinib led to increased radioiodine uptake and retention in a subgroup of patients suffering from radioiodine refractory differentiated thyroid cancer (RR-DTC). We aimed to analyse the effect of selumetinib on the expression of sodium iodide symporter (NIS; SLC5A5) and associated miRNAs in thyroid cancer cells. Methods: Cytotoxicity was assessed by viability assay in TPC1, BCPAP, C643 and 8505C thyroid cancer cell lines. NIS, hsa-let-7f-5p, hsa-miR-146b-5p, and hsa-miR-146b-3p expression was determined by quantitative RT-PCR. NIS protein was detected by Western blot. Radioiodine uptake was performed with a Gamma counter. Results: Selumetinib caused a significant reduction of cell viability in all thyroid cancer cell lines. NIS transcript was restored by selumetinib in all cell lines. Its protein level was found up-regulated in TPC1 and BCPAP cells and down-regulated in C643 and 8505C cells after treatment with selumetinib. Treatment with selumetinib caused a down-regulation of hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p in TPC1 and BCPAP cells. In 8505C cells, a stable or down-regulated hsa-miR-146b-5p was detected after 1h and 48h of treatment. C643 cells showed stable or up-regulated hsa-let-7f-5p, hsa-miR-146b-5p and hsa-miR-146b-3p. Selumetinib treatment caused an increase of radioiodine uptake, which was significant in TPC1 cells. Conclusions: The study shows for the first time that selumetinib restores NIS by the inhibition of its related targeting miRNAs. Further studies are needed to clarify the exact mechanism activated by hsa-miR-146b-5p, hsa-miR-146b-3p and hsa-let7f-5p to stabilise NIS. Restoration of NIS could represent a milestone for the treatment of advanced RR-DTC.

scholarly journals Antitumor activity of Koningic acid in thyroid cancer by inhibiting cellular glycolysis

Endocrine ◽  
2021 ◽  
Author(s):  
Changxin Jing ◽  
Yanyan Li ◽  
Zhifei Gao ◽  
Rong Wang
Keyword(s):  
Thyroid Cancer ◽  
Lactic Acid ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Colony Formation ◽  
Erk Pathway ◽  
Thyroid Cancer Cell ◽  
Thyroid Cancer Cell Lines ◽  
Thyroid Cancer Cells

Abstract Purpose Koningic acid (KA), a sesquiterpene lactone, has been identified as an antimicrobial agent. Recent studies have revealed KA’s antitumor activities in colorectal cancer, leukemia, and lung cancer. However, its antitumor effect in thyroid cancer remains largely unknown. Methods The effects of KA on proliferation, colony formation, apoptosis in thyroid cancer cells were assessed by MTT assay and flow cytometry. After KA treatment, the glycolysis ability of thyroid cancer cells was detected by ECAR, and the glycolytic products and relative ATP levels were measured by ELISA. The underlying mechanisms of antineoplastic activity of KA in thyroid cancer were detected by Western blot. Finally, the antineoplastic activity in vivo was observed in Xenograft mouse models. Results KA inhibited the proliferation, colony formation, and increased cell apoptosis in thyroid cancer cell lines in a dose and time-dependent manner. We verified that the glycolysis ability, ATP production, and lactic acid level in thyroid cancer cells had experienced an extensive decrease after KA treatment. In addition, lactic acid, the metabolite of glycolysis, could weaken the effect of KA on its colony formation ability in C643 thyroid cancer cell line. Our data also showed that KA kills thyroid cancer cells by inhibiting the MAPK/ERK pathway and decreasing Bcl-2 level. By contrast with the control group, the growth of xenograft tumor was dramatically inhibited by KA without obvious drug side effects. Conclusion Our data demonstrate that KA kills thyroid cancer cell lines by inhibiting their glycolysis ability, the MAPK/ERK pathway and the Bcl-2 level and suggest that KA has potential clinical value in thyroid cancer therapy.

scholarly journals Study On the Antitumor Bioactivity of Koningic Acid in Thyroid Cancer in Vivo and in Vitro

2021 ◽  
Author(s):  
Changxin Jing ◽  
Yanyan Li ◽  
Zhifei Gao ◽  
Peng Hou ◽  
Rong Wang
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Colony Formation ◽  
Control Group ◽  
Dependent Manner ◽  
Thyroid Cancer Cell ◽  
Xenograft Tumor ◽  
Antitumor Effects ◽  
Thyroid Cancer Cells

Abstract Purpose: Koningic acid (KA), a sesquiterpene lactone, has been identified as an antimicrobial agent. Recent studies have revealed KA’s antitumor activities in colorectal cancer, leukemia, and lung cancer. However, its antitumor effect in thyroid cancer remains largely unknown. The aim of this study is to test the therapeutic potential of KA in thyroid cancer and explore the mechanisms underlying antitumor effects.Methods: We examined the effects of KA on proliferation, colony formation, apoptosis, ATP deprivation, and xenograft tumor growth in thyroid cancer cells.Results: KA inhibited thyroid cancer cell proliferation, colony formation, and induced cell apoptosis in a dose and time-dependent manner. Our data also showed that KA caused a rapid, extensive decrease of ATP levels in thyroid cancer cells. Growth of xenograft tumor derived from the thyroid cancer cell line C643 in nude mice was significantly inhibited by KA. Importantly, KA treatment did not cause significant liver and kidney damage in mice compared with the control group.Conclusion: KA may be used as an effective and safe agent for thyroid cancer treatment.

scholarly journals The Knockdown of Nrf2 Suppressed Tumor Growth and Increased the Sensitivity to Lenvatinib in Anaplastic Thyroid Cancer

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Zhongqin Gong ◽  
Lingbin Xue ◽  
Minghui Wei ◽  
Zhimin Liu ◽  
Alexander C. Vlantis ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Papillary Thyroid Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Anaplastic Thyroid Cancer ◽  
Thyroid Cancer Cell ◽  
Papillary Thyroid ◽  
Thyroid Cancer Cells

Papillary thyroid cancer can dedifferentiate into a much more aggressive form of thyroid cancer, namely into anaplastic thyroid cancer. Nrf2 is commonly activated in papillary thyroid cancer, whereas its role in anaplastic thyroid cancer has not been fully explored. In this study, we used two cell lines and an animal model to examine the function of Nrf2 in anaplastic thyroid cancer. The role of Nrf2 in anaplastic thyroid cancer was investigated by a series of functional studies in two anaplastic thyroid cancer cell lines, FRO and KAT-18, and further confirmed with an in vivo study. The impact of Nrf2 on the sensitivity of anaplastic thyroid cancer cells to lenvatinib was also investigated to evaluate its potential clinical implication. We found that the expression of Nrf2 was significantly higher in anaplastic thyroid cancer cell line cells than in papillary thyroid cancer cells or normal control cells. Knockdown of Nrf2 in anaplastic thyroid cancer cells inhibited their viability and clonogenicity, reduced their migration and invasion ability in vitro, and suppressed their tumorigenicity in vivo. Mechanistically, knockdown of Nrf2 decreased the expression of Notch1. Lastly, knockdown of Nrf2 increased the sensitivity of anaplastic thyroid cancer cells to lenvatinib. As knockdown of Nrf2 reduced the metastatic and invasive ability of anaplastic thyroid cancer cells by inhibiting the Notch 1 signaling pathway and increased the cancer cell sensitivity to lenvatinib, Nrf2 could be a promising therapeutic target for patients with anaplastic thyroid cancer.

scholarly journals Inhibition of gap junction transfer sensitizes thyroid cancer cells to anoikis

2011 ◽  
Vol 18 (5) ◽  
pp. 613-626 ◽  
Author(s):  
Kirk Jensen ◽  
Aneeta Patel ◽  
Joanna Klubo-Gwiezdzinska ◽  
Andrew Bauer ◽  
Vasyl Vasko
Keyword(s):  
Thyroid Cancer ◽  
Gap Junction ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Thyroid Tissue ◽  
Human Thyroid ◽  
Thyroid Cancer Cell ◽  
Gap Junctional ◽  
Thyroid Cancer Cells

Resistance to anoikis (matrix deprivation-induced apoptosis) is a critical component of the metastatic cascade. Molecular mechanisms underlying resistance to anoikis have not been reported in thyroid cancer cells. For an in vitro model of anoikis, we cultured follicular, papillary, and anaplastic thyroid cancer cell lines on poly-HEMA-treated low-adherent plates. We also performed immunohistochemical analysis of human cancer cells that had infiltrated blood and/or lymphatic vessels. Matrix deprivation was associated with establishment of contacts between floating thyroid cancer cells and formation of multi-cellular spheroids. This process was associated with activation of gap junctional transfer. Increased expression of the gap junction molecule Connexin43 was found in papillary and anaplastic cancer cells forming spheroids. All non-adherent cancer cells showed a lower proliferation rate compared with adherent cells but were more resistant to serum deprivation. AKT was constitutively activated in cancer cells forming spheroids. Inhibition of gap junctional transfer through Connexin43 silencing, or by treatment with the gap junction disruptor carbenoxolone, resulted in loss of pAKT and induction of apoptosis in a cell-type-specific manner. In human thyroid tissue, cancer cells that had infiltrated blood vessels showed morphological similarity to cancer cells forming spheroids in vitro. Intra-vascular cancer cells demonstrated prominent AKT activation in papillary and follicular cancers. Increased Connexin43 immunoreactivity was observed only in intra-vascular papillary cancer cells. Our data demonstrate that establishment of inter-cellular communication contributes to thyroid cancer cell resistance to anoikis. These findings suggest that disruption of gap junctional transfer could represent a potential therapeutic strategy for prevention of metastases.

scholarly journals Demethylation of TMS1 Gene Sensitizes Thyroid Cancer Cells to TRAIL-Induced Apoptosis

2010 ◽  
Vol 24 (11) ◽  
pp. 2241-2242
Author(s):  
Abdul K. Siraj ◽  
Azhar R. Hussain ◽  
Maha Al-Rasheed ◽  
Maqbool Ahmed ◽  
Prashant Bavi ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Methylation Status ◽  
Cancer Cell Lines ◽  
Thyroid Cancer Cell ◽  
Induced Apoptosis ◽  
Thyroid Cancer Cell Lines ◽  
Thyroid Cancer Cells

Abstract Context: TMS1 is a tumor suppressor gene that encodes for caspase recruitment domain containing regulatory protein and has been shown to be hypermethylated in various cancers. However, its methylation status has not been investigated in thyroid cancer. Therefore, we studied the methylation of TMS1 and its functional consequence in thyroid cancer. Design: The methylation status of the promoter region of the TMS1 gene was determined using methylation-specific PCR in 40 papillary thyroid cancer samples, 10 normal thyroid tissue, and seven thyroid cancer cell lines. RT-PCR and Western blot analysis were used to assess the expression levels. 5-aza-2′-deoxycytidine was used to demethylate the thyroid cancer cell lines. Cell viability and apoptosis was determined by dimethylthiazoldiphenyltetra-zoliumbromide and flow cytometry. Results: Twenty-three percent of the papillary thyroid carcinoma samples were found to be methylated for the TMS1 gene. Two of seven thyroid cell lines were either completely or partially methylated for the TMS1 gene. The treatment of methylated thyroid cancer cell lines with 5-aza-2′-deoxycytidine resulted in the demethylation of the TMS1 gene leading to the restoration of its expression. After demethylation, treatment of cells with TNF-related apoptosis-inducing ligand (TRAIL) led to the induction of apoptosis via activation of caspases-8, caspase-3, and poly(ADP-ribose) polymerase. Interestingly, gene silencing of TMS1 using TMS1-specific small interfering RNA prevented TRAIL-mediated apoptosis. Conclusion: Our results demonstrated that the TMSI gene is methylated in thyroid cancer cells and repression of methylation by 5-aza-2′-deoxycytidine restored expression of the TMS1 gene and sensitized cells to TRAIL-induced apoptosis. These findings suggest that the TMS1 gene can be targeted by combination of demethylating agents with TRAIL to induce efficient apoptosis in thyroid cancer cells.

scholarly journals The Role of LINC00284 in the Development of Thyroid Cancer via Its Regulation of the MicroRNA-30d-5p-Mediated ADAM12/Notch Axis

2021 ◽  
Vol 11 ◽  
Author(s):  
Chunmei Hu ◽  
Zhichen Kang ◽  
Lixin Guo ◽  
Fuling Qu ◽  
Rongfeng Qu
Keyword(s):  
Thyroid Cancer ◽  
Notch Signaling ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Cancer Cell ◽  
Notch Signaling Pathway ◽  
Thyroid Cancer Cell ◽  
Cancer Tissues ◽  
Thyroid Cancer Cells

Thyroid cancer is a commonly diagnosed endocrine malignancy with increasing incidence worldwide. Long noncoding RNAs (lncRNAs) are known to function in the invasion and metastasis of thyroid cancer. According to the GSE66783 microarray dataset, long intergenic nonprotein coding RNA 284 (LINC00284) is aberrantly upregulated in thyroid cancer tissues. However, information regarding the specific role of LINC00284 in thyroid cancer remains elusive. Therefore, the current study set out to determine the role of LINC00284 in the development of thyroid cancer, along with an investigation of the underlying molecular mechanism. In parallel with the microarray data from GSE66783, LINC00284 was observed to be expressed at high levels in thyroid cancer cell lines. Moreover, loss-of-function experiments revealed that the downregulation of LINC00284 reduced aldehyde dehydrogenase (ALDH) activity and thyroid cancer cell proliferation, colony formation, and invasiveness, which promoted cell apoptosis. Mechanistically, using dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation (RIP) assays, LINC00284 was identified to competitively bind to microRNA-30d-5p (miR-30d-5p), which was observed to be expressed at low levels in thyroid cancer tissues and cells and directly targets the oncogene a disintegrin and metalloproteinase 12 (ADAM12). Overexpression of miR-30d-5p exerted tumor-suppressive effects on the malignant activity of thyroid cancer cells, changes that were reversed by LINC00284 overexpression or ADAM12 overexpression. Furthermore, LINC00284 activated the Notch signaling pathway by competitively binding to miR-30d-5p and increasing the expression of ADAM12. Finally, by performing in vivo experiments, we found that LINC00284 silencing or miR-30d-5p overexpression suppressed the tumorigenic ability of thyroid cancer cells and that overexpression of miR-30d-5p inhibited the LINC00284-induced tumorigenesis of thyroid cancer cells. Collectively, our findings indicate that LINC00284 competitively binds to miR-30d-5p and activates the ADAM12-dependent Notch signaling pathway, thereby promoting the development of thyroid cancer.

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