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Carles Zafon, Joan Gil, Beatriz Pérez-González and Mireia Jordà

In recent years, cancer genomics has provided new insights into genetic alterations and signaling pathways involved in thyroid cancer. However, the picture of the molecular landscape is not yet complete. DNA methylation, the most widely studied epigenetic mechanism, is altered in thyroid cancer. Recent technological advances have allowed the identification of novel differentially methylated regions, methylation signatures and potential biomarkers. However, despite recent progress in cataloging methylation alterations in thyroid cancer, many questions remain unanswered. The aim of this review is to comprehensively examine the current knowledge on DNA methylation in thyroid cancer and discuss its potential clinical applications. After providing a general overview of DNA methylation and its dysregulation in cancer, we carefully describe the aberrant methylation changes in thyroid cancer and relate them to methylation patterns, global hypomethylation and gene-specific alterations. We hope this review helps to accelerate the use of the diagnostic, prognostic and therapeutic potential of DNA methylation for the benefit of thyroid cancer patients.

Open access

Stephan Felder, Henning Jann, Ruza Arsenic, Timm Denecke, Vikas Prasad, Barbora Knappe-Drzikova, Sebastian Maasberg, Bertram Wiedenmann, Marianne E Pavel, Andreas Pascher and Ulrich-Frank Pape

Although gastric neuroendocrine neoplasias (gNEN) are an orphan disease, their incidence is rising. The heterogeneous clinical course powers the ongoing discussion of the most appropriate classification system and management. Prognostic relevance of proposed classifications was retrospectively analyzed in 142 patients from a single tertiary referral centre. Baseline, management and survival data were acquired for statistical analyses. The distribution according to the clinicopathological typification were: gNEN-1 (n=86/60.6%), gNEN-2 (n=7/4.9%) gNEN-3 (n= 24/16.9%) and gNEN-4 (n=25/17.6%); while hypergastrinemia-associated gNEN-1 and -2 were all low grade tumours (NET-G1/2), formerly termed sporadic gNEN-3 could be subdivided into gNEN-3 with grade 1 or 2 and gNEN-4 with grade 3 (NEC-G3). During follow-up 36 patients died (25%). The mean overall survival (OS) of all gNEN was 14.2 years. The OS differed statistically significant across all subgroups with either classification system. According to UICC 2017 TNM classification OS differed for early and advanced stages, while WHO-grading indicated poorer prognosis for NEC-G3. Cox regression analysis confirmed the independent prognostic validity of either classification system for survival. Particularly careful analysis of the clinical course of gNEN-1 (ECLomas, gastric carcinoids) confirmed their mostly benign, but recurrent and extremely slowly progressive behaviour with low risk of metastasis (7%) and an efficient long-term control by repetitive endoscopic procedures. Our study provides evidence for the validity of current classifications focusing on typing, grading and staging. These are crucial tools for risk stratification, especially to differentiate gNEN-1 as well as sporadic gNET and gNEC (gNEN-3 vs. -4).

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Sisi He, Liqian Ma, Amy E Baek, Anna Vardanyan, Varsha Vembar, Joy J Chen, Adam T Nelson, Joanna E Burdette and Erik R Nelson

There is an urgent need for more effective strategies to treat ovarian cancer. Elevated cholesterol levels are associated with a decreased progression-free survival time (PFS) while statins are protective. 27-Hydroxycholesterol (27HC), a primary metabolite of cholesterol, has been shown to modulate the activities of the estrogen receptors (ERs) and liver x receptors (LXRs) providing a potential mechanistic link between cholesterol and ovarian cancer progression. We found that high expression of CYP27A1, the enzyme responsible for the synthesis of 27HC, was associated with decreased PFS, while high expression of CYP7B1, responsible for 27HC catabolism, was associated with increased PFS. However, 27HC decreased the cellular proliferation of various ovarian cancer cell lines in an LXR-dependent manner. Intriguingly, ID8 grafts were unable to effectively establish in CYP27A1−/− mice, indicating involvement of the host environment. Tumors from mice treated with 27HC had altered myeloid cell composition, and cells from the marrow stem cell lineage were found to be responsible for the effects in CYP27A1−/− mice. While inhibition of CYP27A1 or immune checkpoint did not significantly alter tumor size, their combination did, thereby highlighting this axis as a therapeutic target.

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Meng Ji, Yanli Yao, Anan Liu, Ligang Shi, Danlei Chen, Liang Tang, Guang Yang, Xing Liang, Junfeng Peng and Chenghao Shao

Pancreatic neuroendocrine neoplasms (pNENs) are endocrine tumors arising in pancreas and is the most common neuroendocrine tumors. Mounting evidence indicates lncRNA H19 could be a determinant of tumor progression. However, the expression and mechanism of H19 and the relevant genes mediated by H19 in pNENs remain undefined. Microarray analysis was conducted to identify the differentially expressed lncRNAs in pNENs. H19 expression was analyzed in 39 paired pNEN tissues by qPCR. The biological role of H19 was determined by functional experiments. RNA pulldown, mass spectroscopy and RNA immunoprecipitation were performed to confirm the interaction between H19 and VGF. RNA-seq assays were performed after knockdown H19 or VGF. H19 was significantly upregulated in pNEN tissues with malignant behaviors, and the upregulation predicted poor prognosis in pNENs. In vitro and in vivo data showed that H19 overexpression promoted tumor growth and metastasis, whereas H19 knockdown led to the opposite phenotypes. H19 interacted with VGF, which was significantly upregulated in pNENs, and higher VGF expression was markedly related to poor differentiation and advanced stage. Furthermore, VGF was downregulated when H19 was knocked down, and VGF promoted cell proliferation, migration and invasion. Mechanistic investigations revealed that H19 activated PI3K/AKT/CREB signaling and promoted pNEN progression by interacting with VGF. These findings indicate that H19 is a promising prognostic factor in pNENs with malignant behaviors and functions as an oncogene via the VGF-mediated PI3K/AKT/CREB pathway. In addition, our study implies that VGF may also serve as a candidate prognostic biomarker and therapeutic target in pNENs.

Free access

Jae Hyun Park and Jong Ho Yoon

The extent of thyroid surgery for patients with low- and intermediate-risk differentiated thyroid carcinoma (DTC), with a primary tumour <4 cm and no extrathyroidal extension (ETE) or lymph node (LN) metastases, has shifted in a more conservative direction. However, clinicopathological risk factors, including microscopic ETE, aggressive histology, vascular invasion in papillary thyroid carcinoma (PTC) and intermediate volume of LN metastases, can only be identified after completing thyroid lobectomy. It is controversial whether patients with these risk factors should immediately undergo complete thyroidectomy and/or radioactive iodine remnant ablation or should be monitored without further treatments. Data are conflicting about the prognostic impact of these risk factors on clinical DTC outcomes. Notably, the recurrence rate in patients who underwent thyroid lobectomy is low and the few recurrences that develop during long-term follow-up can readily be detected by neck ultrasonography and treated by salvage surgery with no impact on survival. These findings suggest that a more conservative approach may be a preferred management strategy over immediate completion surgery, despite a slightly higher risk of structural recurrence. Regarding follow-up of post-lobectomy DTC patients, it is reasonable that an initial risk stratification system based on clinicohistological findings be used to guide the short-term follow-up prior to evaluating the response to initial therapy and that the dynamic risk stratification system based on the response to initial therapy be used to guide long-term follow-up.

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Nunki Hassan, Jing Ting Zhao, Anthony Glover, Bruce G Robinson and Stan B Sidhu

Adrenocortical carcinoma (ACC) has high recurrence rates and poor prognosis with limited response to conventional cancer therapy. Recent contributions of high-throughput transcriptomic profiling identified microRNA-497 (miR-497) as significantly underexpressed, while lncRNA MALAT1 (metastasis-associated lung adenocarcinoma transcript 1) as overexpressed in ACC. miR-497 is located in the chromosomal region 17p13.1, in which there is a high frequency of loss of heterozygosity in ACC. We aim to investigate the interaction of miR-497 and MALAT1 in ACC and its functional roles in the process of tumourigenesis. In this study, we demonstrated miR-497 post-transcriptionally repressed MALAT1 while MALAT1 also competes for miR-497 binding to its molecular target, EIF4E (eukaryotic translation initiation factor 4E). We showed that overexpression of miR-497 and silencing of MALAT1 suppressed cellular proliferation and induced cell cycle arrest through downregulation of EIF4E expression. Furthermore, MALAT1 directly binds to SFPQ (splicing factor proline and glutamine rich) protein, indicating its multifaceted roles in ACC pathophysiology. This is the first study to identify the feedback axis of miR-497-MALAT1/EIF4E in ACC tumourigenesis, providing novel insights into the molecular functions of noncoding RNAs in ACC.

Free access

Hao Fu, Lin Cheng, Yuchen Jin and Libo Chen

Thyrotoxicosis with concomitant thyroid cancer is rare and poorly recognized, which may result in delayed diagnosis, inappropriate treatment and even poor prognosis. To provide a comprehensive guidance for clinicians, the etiology, pathogenesis, diagnosis and treatment of this challenging setting were systematically reviewed. According to literatures available, the etiologies of thyrotoxicosis with concomitant thyroid cancer were categorized into Graves’ disease with concurrent differentiated thyroid cancer (DTC) or medullary thyroid cancer, Marine–Lenhart Syndrome with coexisting DTC, Plummer’s disease with concomitant DTC, amiodarone-induced thyrotoxicosis with concomitant DTC, central hyperthyroidism with coexisting DTC, hyperfunctioning metastases of DTC and others. The underlying causal mechanisms linking thyrotoxicosis and thyroid cancer were elucidated. Medical history, biochemical assessments, radioiodine uptake, anatomic and metabolic imaging and ultrasonography-guided fine-needle aspiration combined with pathological examinations were found to be critical for precise diagnosis. Surgery remains a mainstay in both tumor elimination and control of thyrotoxicosis, while anti-thyroid drugs, beta-blockers, 131I, glucocorticoids, plasmapheresis, somatostatin analogs, dopamine agonists, radiation therapy, chemotherapy and tyrosine kinase inhibitors should also be appropriately utilized as needed.

Free access

Anna Angelousi, Eva Kassi, Narjes Ansari-Nasiri, Harpal Randeva, Gregory Kaltsas and George Chrousos

Circadian rhythms at a central and peripheral level are operated by transcriptional/translational feedback loops involving a set of genes called ‘clock genes’ that have been implicated in the development of several diseases, including malignancies. Dysregulation of the Clock system can influence cancer susceptibility by regulating DNA damage and repair mechanisms, as well as apoptosis. A number of oncogenic pathways can be dysregulated via clock genes’ epigenetic alterations, including hypermethylation of clock genes’ promoters or variants of clock genes. Clock gene disruption has been studied in breast, lung and prostate cancer, and haematological malignancies. However, it is still not entirely clear whether clock gene disruption is the cause or the consequence of tumourigenesis and data in endocrine neoplasms are scarce. Recent findings suggest that clock genes are implicated in benign and malignant adrenocortical neoplasias. They have been also associated with follicular and papillary thyroid carcinomas and parathyroid adenomas, as well as pituitary adenomas and craniopharyngiomas. Dysregulation of clock genes is also encountered in ovarian and testicular tumours and may also be related with their susceptibility to chemotherapeutic agents. The most common clock genes that are implicated in endocrine neoplasms are PER1, CRY1; in most cases their expression is downregulated in tumoural compared to normal tissues. Although there is still a lot to be done for the better understanding of the role of clock genes in endocrine tumourigenenesis, existing evidence could guide research and help identify novel therapeutic targets aiming mainly at the peripheral components of the clock gene system.

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Aura D Herrera-Martínez, Rosanna van den Dungen, Fadime Dogan-Oruc, Peter M van Koetsveld, Michael D Culler, Wouter W de Herder, Raúl M Luque, Richard A Feelders and Leo J Hofland

Control of symptoms related to hormonal hypersecretion by functioning neuroendocrine tumors (NETs) is challenging. New therapeutic options are required. Since novel in vitro tumor models seem to better mimic the tumor in vivo conditions, we aimed to study the effect of somatostatin and dopamine receptor agonists (octreotide and cabergoline, respectively) and novel somatostatin-dopamine chimeric multi-receptor drugs (BIM-065, BIM-23A760) using 2D (monolayer) and 3D (spheroids) cultures. Dose–response studies in 2D and 3D human pancreatic NET cell cultures (BON-1 and QGP-1) were performed under serum-containing and serum-deprived conditions. Cell proliferation, somatostatin and dopamine receptor expression (SSTs and D2R), apoptosis, lactate dehydrogenase, as well as serotonin and chromogranin A (CgA) release were assessed. The following results were obtained. 3D cultures of BON-1/QGP-1 allowed better cell survival than 2D cultures in serum-deprived conditions. SSTs and D2R mRNA levels were higher in the 3D model vs 2D model. Octreotide/cabergoline/BIM-065/BIM-23A760 treatment did not affect cell growth or spheroid size. In BON-1 2D-cultures, only BIM-23A760 significantly inhibited CgA release –this effect being more pronounced in 3D cultures. In BON-1 2D cultures, cabergoline/BIM-065/BIM-23A760 treatment decreased serotonin release (maximal effect up to 40%), being this effect again more potent in 3D cultures (up to 67% inhibition; with BIM-23A760 having the most potent effects). In QGP-1, cabergoline/BIM-065 treatment decreased serotonin release only in the 3D model. In conclusion, cultures of NET 3D spheroids represent a promising method for evaluating cell proliferation and secretion in NET cell-line models. Compared to 2D models, 3D models grow relatively serum independent. In 3D model, SST-D2R multi-receptor targeting drugs inhibit CgA and serotonin secretion, but not NET cell growth.

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Emmanuelle Fleurot, Caroline Goudin, Vincent Hanoux, Pierre-Jacques Bonnamy and Jérôme Levallet

Breast cancer (BC) is the primary cause of cancer-related mortality among women. Patients who express the estrogen receptor (ER), which mediates the tumorigenic effects of estrogens, respond to antihormonal therapy. Loss of ER expression or acquired resistance to E2 is associated with aggressive malignant phenotypes, which lead to relapse. These BC subtypes overexpress syndecan-1 (SDC1), a transmembrane heparan sulfate proteoglycan that mediates angiogenesis as well as the proliferation and invasiveness of cancer cells. We showed here that the activation of ER-alpha (ERα) by estrogens induces downregulation of SDC1 expression in ER(+) MCF7 cells but not in T47D cells. Loss of ERα expression, induced by RNA interference or a selective ER downregulator, led to subsequent SDC1 overexpression. E2-dependent downregulation of SDC1 expression required de novo protein synthesis and was antagonized by treatment with BAY 11-7085, an irreversible inhibitor of IκBα phosphorylation, which inhibits the activation of NFκB. Downregulation of SDC1 expression required ERα and activation of IKK, but was independent to downstream transcriptional regulators of NFκB. BAY 11-7085 prevented E2-mediated phosphorylation of ERα on Ser118, increasing its proteasomal degradation, suggesting that IKK stabilized E2-activated ERα, leading to subsequent downregulation of SDC1 expression. Our results showed that sustained ER signaling inhibits SDC1 expression. Such antagonism elucidates the inverse correlation between SDC1 and ER expression in ER(+) BC as well as the overexpression of SDC1 in hormone receptor-negative BC subtypes with the most aggressive phenotypes. These results identify SDC1 as an attractive therapeutic target for BC as well as for other endocrine-associated cancers.