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Special Issue "Recent Advances in Thyroid Cancer Research"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 31 December 2021.

Special Issue Editor

Special Issue Information

Dear Colleagues,

Thyroid cancer (TC) comprises malignant tumours of the thyroid gland. TC is classified into several categories: first, differentiated tumors covering papillary, follicular and Hürthle cell cancer; second, medullary; and third, anaplastic TC. The American Cancer Society’s most recent estimates for TC in the US for 2021 are: 1. About 44,280 new cases (12,150 in men and 32,130 in women) and 2. about 22,200 deaths (1,050 men and 1,150 women). The most common type is the papillary thyroid carcinoma, with a share of 80–90% in all TC.

In recent years, studies in the field of TC have been performed in order to identify and verify thyroid specific biomarkers, as well as cancer-specific changes in gene expression patterns and alterations of the protein content. Furthermore, new drugs, small molecules and antibodies were developed and tested in vitro and in vivo. Trials investigated the ratio between therapeutic and adverse effects. Tyrosine kinase inhibitors (TKI) have become a new therapeutic option for both differentiated and medullary TC. In the last few years, new substances for targeted systemic therapy have been approved after their efficacy was demonstrated in phase III trials. Most of them produced a moderate response. However, adverse effects are common. TKI are used in patients with advanced metastatic, radioiodine (RAI)-refractory TC.

In this Special Issue, studies using animal or cell culture models to investigate molecular mechanisms of TC will be published. This Special Issue will also cover reports on patients, providing novel mechanistic insights into the underlying pathogenesis or new aspects that may impact clinical therapy.

Prof. Dr. Daniela Grimm
Guest Editor

Manuscript Submission Information

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Keywords

  • Thyroid cancer
  • Cell Biology
  • OMICS investigations
  • Cell Signaling
  • Biomarker
  • Tyrosine kinase inhibitors
  • Molecular biology
  • In vitro studies
  • Animal studies
  • Drug testing

Published Papers (4 papers)

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Research

Article
The CellBox-2 Mission to the International Space Station: Thyroid Cancer Cells in Space
Int. J. Mol. Sci. 2021, 22(16), 8777; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22168777 - 16 Aug 2021
Viewed by 413
Abstract
A spaceflight to the International Space Station (ISS) is a dream of many researchers. We had the chance to investigate the effect of real microgravity (CellBox-2 Space mission) on the transcriptome and proteome of FTC-133 human follicular thyroid cancer cells (TCC). The cells [...] Read more.
A spaceflight to the International Space Station (ISS) is a dream of many researchers. We had the chance to investigate the effect of real microgravity (CellBox-2 Space mission) on the transcriptome and proteome of FTC-133 human follicular thyroid cancer cells (TCC). The cells had been sent to the ISS by a Falcon 9 rocket of SpaceX CRS-13 from Cape Canaveral (United States) and cultured in six automated hardware units on the ISS before they were fixed and returned to Earth. Multicellular spheroids (MCS) were detectable in all spaceflight hardware units. The VCL, PXN, ITGB1, RELA, ERK1 and ERK2 mRNA levels were significantly downregulated after 5 days in space in adherently growing cells (AD) and MCS compared with ground controls (1g), whereas the MIK67 and SRC mRNA levels were both suppressed in MCS. By contrast, the ICAM1, COL1A1 and IL6 mRNA levels were significantly upregulated in AD cells compared with 1g and MCS. The protein secretion measured by multianalyte profiling technology and enzyme-linked immunosorbent assay (AngiogenesisMAP®, extracellular matrix proteins) was not significantly altered, with the exception of elevated angiopoietin 2. TCC in space formed MCS, and the response to microgravity was mainly anti-proliferative. We identified ERK/RELA as a major microgravity regulatory pathway. Full article
(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)
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Article
Loss of ZNF677 Expression Is an Independent Predictor for Distant Metastasis in Middle Eastern Papillary Thyroid Carcinoma Patients
Int. J. Mol. Sci. 2021, 22(15), 7833; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22157833 - 22 Jul 2021
Viewed by 405
Abstract
Thyroid cancer incidence has increased in recent decades. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Approximately 30% of PTC patients develop recurrence or distant metastasis and tend to have poor prognosis. Therefore, the identification of targetable biomarkers in [...] Read more.
Thyroid cancer incidence has increased in recent decades. Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer. Approximately 30% of PTC patients develop recurrence or distant metastasis and tend to have poor prognosis. Therefore, the identification of targetable biomarkers in this subset of patients is of great importance. Accumulating evidence indicates that zinc finger protein 677 (ZNF677), which belongs to the zinc finger protein family, is an important effector during the progression of multiple malignancies. However, its role in Middle Eastern PTC patients has not been fully illustrated. Here, we uncovered the molecular mechanism and the clinical impact of ZNF677 expression in a large cohort of more than 1200 Middle Eastern PTC and 15 metastatic tissues. We demonstrated that ZNF677 is frequently downregulated in primary PTC (13.6%, 168/1235) and showed that complete loss of expression of ZNF677 is significantly associated with aggressive clinico-pathological markers such as extrathyroidal extension (p = 0.0008) and distant metastases (p < 0.0001). We also found a significantly higher incidence of ZNF677 loss in primary tumors with distant metastases (33.3%; p < 0.0001) as well as in distant metastatic tissues (46.7%; p = 0.0002) compared to the overall cohort (13.6%). More importantly, PTC with loss of ZNF677 expression showed significantly lower metastasis-free survival (p = 0.0090). Interestingly, on multivariate logistic regression analysis, ZNF677 loss was an independent predictor of distant metastasis in PTC (Odds ratio = 2.60, 95% Confidence interval = 1.20–5.62, p = 0.0155). In addition, we found a significant association between ZNF677 loss and phospho-AKT expression (p < 0.0001). Our functional molecular results suggest that ZNF677 acts as a tumor suppressor, mediating its effect by inhibiting AKT phosphorylation. Taken together, our results highlight the pivotal role played by ZNF677 during carcinogenesis and metastasis formation in Middle Eastern PTC patients. Full article
(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)
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Article
FOXE1-Dependent Regulation of Macrophage Chemotaxis by Thyroid Cells In Vitro and In Vivo
Int. J. Mol. Sci. 2021, 22(14), 7666; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147666 - 17 Jul 2021
Viewed by 709
Abstract
Forkhead box E1 (FOXE1) is a lineage-restricted transcription factor involved in thyroid cancer susceptibility. Cancer-associated polymorphisms map in regulatory regions, thus affecting the extent of gene expression. We have recently shown that genetic reduction of FOXE1 dosage modifies multiple thyroid cancer [...] Read more.
Forkhead box E1 (FOXE1) is a lineage-restricted transcription factor involved in thyroid cancer susceptibility. Cancer-associated polymorphisms map in regulatory regions, thus affecting the extent of gene expression. We have recently shown that genetic reduction of FOXE1 dosage modifies multiple thyroid cancer phenotypes. To identify relevant effectors playing roles in thyroid cancer development, here we analyse FOXE1-induced transcriptional alterations in thyroid cells that do not express endogenous FOXE1. Expression of FOXE1 elicits cell migration, while transcriptome analysis reveals that several immune cells-related categories are highly enriched in differentially expressed genes, including several upregulated chemokines involved in macrophage recruitment. Accordingly, FOXE1-expressing cells induce chemotaxis of co-cultured monocytes. We then asked if FOXE1 was able to regulate macrophage infiltration in thyroid cancers in vivo by using a mouse model of cancer, either wild type or with only one functional FOXE1 allele. Expression of the same set of chemokines directly correlates with FOXE1 dosage, and pro-tumourigenic M2 macrophage infiltration is decreased in tumours with reduced FOXE1. These data establish a novel link between FOXE1 and macrophages recruitment in the thyroid cancer microenvironment, highlighting an unsuspected function of this gene in the crosstalk between neoplastic and immune cells that shape tumour development and progression. Full article
(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)
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Article
V600EBRAF Inhibition Induces Cytoprotective Autophagy through AMPK in Thyroid Cancer Cells
Int. J. Mol. Sci. 2021, 22(11), 6033; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116033 - 03 Jun 2021
Cited by 1 | Viewed by 859
Abstract
The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where V600EBRAF is a main oncogene. Here, we analyse the effect of V600EBRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of [...] Read more.
The dysregulation of autophagy is important in the development of many cancers, including thyroid cancer, where V600EBRAF is a main oncogene. Here, we analyse the effect of V600EBRAF inhibition on autophagy, the mechanisms involved in this regulation and the role of autophagy in cell survival of thyroid cancer cells. We reveal that the inhibition of V600EBRAF activity with its specific inhibitor PLX4720 or the depletion of its expression by siRNA induces autophagy in thyroid tumour cells. We show that V600EBRAF downregulation increases LKB1-AMPK signalling and decreases mTOR activity through a MEK/ERK-dependent mechanism. Moreover, we demonstrate that PLX4720 activates ULK1 and increases autophagy through the activation of the AMPK-ULK1 pathway, but not by the inhibition of mTOR. In addition, we find that autophagy blockade decreases cell viability and sensitize thyroid cancer cells to V600EBRAF inhibition by PLX4720 treatment. Finally, we generate a thyroid xenograft model to demonstrate that autophagy inhibition synergistically enhances the anti-proliferative and pro-apoptotic effects of V600EBRAF inhibition in vivo. Collectively, we uncover a new role of AMPK in mediating the induction of cytoprotective autophagy by V600EBRAF inhibition. In addition, these data establish a rationale for designing an integrated therapy targeting V600EBRAF and the LKB1-AMPK-ULK1-autophagy axis for the treatment of V600EBRAF-positive thyroid tumours. Full article
(This article belongs to the Special Issue Recent Advances in Thyroid Cancer Research)
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