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Background: Mitochondrial stress is known to activate the mitochondrial unfolded protein response (UPRmt). The UPRmt results in the secretion of mitochondrial cytokines (mitokines), which can promote a hormetic response cell nonautonomously, and has been reported to be protumorigenic. Growth differentiation factor 15 (GDF15) is a well-characterized mitokine, which is reported to have a mitohormetic effect. Thus, we investigated whether GDF15 induction could prime a subpopulation of thyroid cancer cells to provide invasive advantages. Methods: The UPRmt, including mitokine expression, was assessed in the context of thyroid cancer in vitro and in vivo. GDF15 expression in 266 patients with papillary thyroid carcinoma (PTC) was determined by immunohistochemistry. The serum levels of GDF15 were measured in healthy subjects and PTC patients. In addition, our own and The Cancer Genome Atlas data were analyzed to determine the expression level of GDF15 in thyroid cancers. The role of GDF15 in tumor aggressiveness was investigated by observing the effects of GDF15 knockdown in BCPAP, TPC-1, 8505C, and FRO cells. Results: Pharmacological inhibition of mitochondrial oxidative phosphorylation function in thyroid cancer cells robustly increased GDF15 expression. The expression of GDF15 was associated with activation of the mitochondrial integrated stress response pathway in PTC patients. Circulating GDF15 levels were significantly higher in PTC patients than in the controls, and tumor expression of GDF15 was related to tumor aggressiveness. In vitro and in vivo knockdown of GDF15 in a thyroid cancer model showed decreased viability, migration, and invasion compared with the control cells via regulation of STAT3. Conclusions: In this study, we demonstrated that GDF15 is a mitokine induced in thyroid cancer cells upon mitochondrial stress. GDF15-induced STAT3 activation determined tumor progression in thyroid cancer. The GDF15-STAT3 signaling axis may be a target in aggressiveness of thyroid cancer.

Background: A Korean Multicenter Prospective cohort study of Active Surveillance or Surgery (KoMPASS) for papillary thyroid microcarcinomas (PTMCs) has been initiated. The aim is to compare clinical outcomes between active surveillance (AS) and an immediate lobectomy for low-risk PTMCs. We here outline the detailed protocol for this study.Methods: Adult patients with a cytopathologically confirmed PTMC sized 6.0 to 10.0 mm by ultrasound (US) will be included. Patients will be excluded if they have a suspicious extra-thyroidal extension or metastasis of a PTMC or multiple thyroid nodules or other thyroid diseases which require a total thyroidectomy. Printed material describing the prognosis of PTMCs, and the pros and cons of each management option, will be provided to eligible patients to select their preferred intervention. For the AS group, thyroid US, thyroid function, and quality of life (QoL) parameters will be monitored every 6 months during the first year, and then annually thereafter. Disease progression will be defined as a ≥3 mm increase in maximal diameter of a PTMC, or the development of new thyroid cancers or metastases. If progression is detected, patients should undergo appropriate surgery. For the lobectomy group, a lobectomy with prophylactic central neck dissection will be done within 6 months. After initial surgery, thyroid US, thyroid function, serum thyroglobulin (Tg), anti-Tg antibody, and QoL parameters will be monitored every 6 months during the first year and annually thereafter. Disease progression will be defined in these cases as the development of new thyroid cancers or metastases.Conclusion: KoMPASS findings will help to confirm the role of AS, and develop individualized management strategies, for low-risk PTMCs.

Background Brn3a/Pou4f1 is a class IV POU domain-containing transcription factor and has been found to be expressed in a variety of cancers. However, the mechanism and action of Brn3a in thyroid cancer has not been investigated. Purpose To investigate the role of Brn3a in thyroid cancer progression and its clinical implication. Methods We examined Brn3a expression status in patients with thyroid cancer and analyzed relationships between Brn3a expression and clinicopathological findings using The Cancer Genome Atlas (TCGA) database. For functional in vitro analysis, proliferation, migration, invasion assay, and Western blotting were performed after overexpression or suppression of Brn3a. Results The promoter hypermethylation of Brn3a was found in patients with aggressive thyroid cancer and Brn3a was downregulated in tissues of patients with thyroid cancer. In TCGA database, the low-Brn3a-expression group revealed a more aggressive phenotype, including T stage and extrathyroid extension when compared with the high-Brn3a-expression group. Overexpression of Brn3a suppressed cell migration and invasion via regulation of epithelial-mesenchymal transition (EMT)-associated proteins in thyroid cancer cell lines. Brn3a overexpression also downregulated signal transducer and activator of transcription 3 (STAT3) signaling through suppression of tyrosine-protein kinase Met (c-MET). In contrast, knockdown of Brn3a by small interfering ribonucleic acid (siRNA) significantly increased cell migration and invasion through upregulation of c-MET/STAT3. These results imply that Brn3a suppresses tumor metastasis via c-MET/STAT3 inhibition and EMT suppression in thyroid cancer. Conclusions Our findings show that Brn3a is a potential tumor suppressor that leads to reduced cancer cell migration and invasion in thyroid cancer. Elucidation of the Brn3a-regulated cancer pathways may therefore provide novel therapeutic strategies to control thyroid cancer metastasis.

(1) Background: Nonthermal plasma (NTP) induces cell death in various types of cancer cells, providing a promising alternative treatment strategy. Although recent studies have identified new mechanisms of NTP in several cancers, the molecular mechanisms underlying its therapeutic effect on thyroid cancer (THCA) have not been elucidated. (2) Methods: To investigate the mechanism of NTP-induced cell death, THCA cell lines were treated with NTP-activated medium -(NTPAM), and gene expression profiles were evaluated using RNA sequencing. (3) Results: NTPAM upregulated the gene expression of early growth response 1 (EGR1). NTPAM-induced THCA cell death was enhanced by EGR1 overexpression, whereas EGR1 small interfering RNA had the opposite effect. NTPAM-derived reactive oxygen species (ROS) affected EGR1 expression and apoptotic cell death in THCA. NTPAM also induced the gene expression of growth arrest and regulation of DNA damage-inducible 45&alpha, (GADD45A) gene, and EGR1 regulated GADD45A through direct binding to its promoter. In xenograft in vivo tumor models, NTPAM inhibited tumor progression of THCA by increasing EGR1 levels. (4) Conclusions: Our findings suggest that NTPAM induces apoptotic cell death in THCA through a novel mechanism by which NTPAM-induced ROS activates EGR1/GADD45&alpha, signaling. Furthermore, our data provide evidence that the regulation of the EGR1/GADD45&alpha, axis can be a novel strategy for the treatment of THCA.

Background Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy. Methods This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years. Conclusion The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.

Objective Neuropilin-2 (NRP2) is a coreceptor of vascular endothelial growth factor-C/D (VEGF-C/D) and plays the important role in the development of lymphatic endothelial cells, as well as neuronal development. NRP2 is known to affect aggressiveness by increasing expression in various human cancers, but the role of NRP2 in thyroid cancer is not fully understood. The purpose of this study was to investigate the NRP2 expression and its role in regulating the tumor aggressiveness in the papillary thyroid carcinoma (PTC). Methods The NRP2 expression and its clinicopathologic correlation to PTC was determined using the data from the 262 PTC patients at a tertiary referral medical center and The Cancer Genome Atlas (TCGA) database. The potential role of NRP2 in modulating tumor growth, invasion, and metastasis in PTC was examined by using small interfering RNA (siRNA)-mediated knockdown of NRP2. Results High expression of NRP2 was significantly associated with capsular invasion, lymphovascular invasion, lymph node metastasis, 5 or more metastatic lymph nodes, and recurrence in PTC patients. In TCGA data, the higher NRP2 expression group was significantly associated with extrathyroid extension, lymph node metastasis, and BRAFV600E mutation. The siRNA mediated knockdown of NRP2 in the PTC cells reduced the cell proliferation, migration and invasion. We also have confirmed that NRP2 knockdown suppressed epithelial-mesenchymal transition (EMT) by regulating AKT and ERK phosphorylation signaling pathways. Conclusion Our results suggest that NRP2 regulates tumor progression in PTC and may act as a predictive factor for aggressiveness of PTC.

Fibroblast growth factor 21 (FGF21) plays important roles in regulating glucose, lipid, and energy metabolism, however, its effects in tumors remain poorly understood. To understand the role of FGF21 in regulating tumor aggressiveness in thyroid cancer, serum levels of FGF21 were measured in healthy subjects and patients with papillary thyroid cancer (PTC), and expression levels of FGF21, FGF receptors (FGFRs), and &beta, klotho (KLB) were investigated in human thyroid tissues. The cell viability, migrating cells, and invading cells were measured in PTC cells after treatment with recombinant FGF21. Higher serum levels of FGF21 were found in patients with thyroid cancer than in control participants, and were significantly associated with body mass index (BMI), fasting glucose levels, triglyceride levels, tumor stage, lymphovascular invasion, and recurrence. Serum FGF21 levels were positively correlated with the BMI in patients with PTC, and significantly associated with recurrence. Recombinant FGF21 led to tumor aggressiveness via activation of the FGFR signaling axis and epithelial-to-mesenchymal transition (EMT) signaling in PTC cells, and AZD4547, an FGFR tyrosine kinase inhibitor, attenuated the effects of FGF21. Hence, FGF21 may be a new biomarker for predicting tumor progression, and targeting FGFR may be a novel therapy for the treatment of obese patients with PTC.

The purpose of this systematic review and meta-analysis was to determine the optimal extent of lateral neck dissection in patients with well-differentiated thyroid carcinoma with clinically confirmed lateral neck lymph node metastases. All studies reporting the distribution of metastatic lymph nodes in level IIb or level V, complication rate, recurrence rate, or clinical outcomes according to the extent of lateral neck dissection were collected from MEDLINE and Embase databases. Two reviewers independently retrieved articles, extracted data, and assessed the quality of the studies. A total of 40 criteria-meeting studies were included in the systematic review and meta-analysis, representing a total of 6 027 patients. The distribution of metastatic lymph nodes was 13.7% (95% confidence interval [CI]: 8.2-21.9%) in level IIb and 22.1% (95% CI: 18.6-26.1%) in level V. Shoulder syndrome complication showed a tendency to increase when comprehensive neck dissection was performed. The recurrence rate was 11.2% (95% CI: 8.4-14.9%) in the comprehensive neck dissection group and 11.0% (95% CI: 4.2-26.1%) in the selective neck dissection group. Clinical outcomes showed no difference between groups. In conclusion, selective neck dissection may be considered in patients with well-differentiated thyroid carcinoma with lateral neck lymph node metastases without any other risk factors.

Primary thyroid cancers including papillary, follicular, poorly differentiated, and anaplastic carcinomas show substantial differences in biological and clinical behaviors. Even in the same pathological type, there is wide variability in the clinical course of disease progression. The molecular carcinogenesis of thyroid cancer has advanced tremendously in the last decade. However, specific inhibition of oncogenic pathways did not provide a significant survival benefit in advanced progressive thyroid cancer that is resistant to radioactive iodine therapy. Accumulating evidence clearly shows that cellular energy metabolism, which is controlled by oncogenes and other tumor-related factors, is a critical factor determining the clinical phenotypes of cancer. However, the role and nature of energy metabolism in thyroid cancer remain unclear. In this article, we discuss the role of cellular energy metabolism, particularly mitochondrial energy metabolism, in thyroid cancer. Determining the molecular nature of metabolic remodeling in thyroid cancer may provide new biomarkers and therapeutic targets that may be useful in the management of refractory thyroid cancers.

The signaling pathway involving the R-spondins and its cognate receptor, GPR48/LGR4, is crucial in development and carcinogenesis. However, the functional implications of the R-spondin-GPR48/LGR4 pathway in thyroid remain to be identified. The aim of this study was to investigate the role of R-spondin-GPR48/LGR4 signaling in papillary thyroid carcinomas. We retrospectively reviewed a total of 214 patients who underwent total thyroidectomy and cervical lymph node dissection for papillary thyroid carcinoma. The role of GPR48/LGR4 in proliferation and migration was examined in thyroid cancer cell lines. R-spondin 2, and GPR48/LGR4 were expressed at significantly higher levels in thyroid cancer than in normal controls. Elevated GPR48/LGR4 expression was significantly associated with tumor size (P=0.049), lymph node metastasis (P=0.004), recurrence (P=0.037), and the BRAFV600E mutation (P=0.003). Moreover, high GPR48/LGR4 expression was an independent risk factor for lymph node metastasis (P=0.027) and the BRAFV600E mutation (P=0.009). in vitro assays demonstrated that elevated expression of GPR48/LGR4 promoted proliferation and migration of thyroid cancer cells, whereas downregulation of GPR48/LGR4 decreased proliferation and migration by inhibition of the β-catenin pathway. Moreover, treatment of thyroid cancer cells with exogenous R-spondin 2 induced activation of the β-catenin pathway through GPR48/LGR4. The R-spondin 2-GPR48/LGR4 signaling axis also induced the phosphorylation of ERK, as well as phosphorylation of LRP6 and serine 9 of GSK3β. Our findings demonstrate that upregulation of the R-spondin 2-GPR48/LGR4 pathway contributes to tumor aggressiveness in papillary thyroid carcinoma by promoting ERK phosphorylation, suggesting that this pathway represents a novel therapeutic target for treatment of differentiated thyroid cancer.

Purpose: As mitochondrial dysfunction is an integral component during the initial stages of tumorigenesis, mechanistic insight on the interaction between these two pathways may lead to novel therapeutic approaches. The aim of this study is to investigate the role of GDF15, the putative mitokine factor in thyroid tumorigenesis. Methods: Expression levels of GDF15 was investigated using The Cancer Genome Atlas database. The role of GDF15 in tumor aggressiveness was investigated by analyzing the effects of knock-down of GDF15 on proliferation, migration, and invasion of thyroid cancer cells. Serum levels of GDF15 were measured in healthy subjects and patients with papillary thyroid cancer (PTC), and expression of GDF15 by IHC was investigated in PTC samples. To investigate the exact mechanism of GDF15 in thyroid cancer, both IPA analysis and GSEA analysis were performed using TCGA database and RNA seq data from Chungnam national university hospital. Results: TCGA data revealed the higher expression of GDF15 in tumor samples compared to in paired non-tumor samples. Thyroid cancer cells with knock-down of GDF15 revealed the decrease of proliferation, migration, and invasion compared to control cells via regulation of STAT3. Higher serum levels of GDF15 were found in patients with thyroid cancer than in control participants, and were significantly associated with tumor stage, lymphovascular invasion, and recurrence. In addition, patients with high GDF15 expression by IHC revealed the aggressive phenotype compared to patients with low GDF15 expression. Conclusions: GDF15 is a new biomarker for predicting tumor progression, and therapies targeting GDF15 may be effective for treating thyroid cancer. Citation Format: Yea Eun Kang, Jae Won Chang, Lihua Liu, Kyoungmin Lee, Mi Ae Lim, Seung-Nam Jung, Chan Oh, Ho-Ryun Won, Minho Shong, Bon Seok Koo. GDF15, the putative mitokine factor, promotes tumor progression in thyroid cancer via STAT3 regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 795.