ALKBH5-induced circular RNA NRIP1 promotes glycolysis in thyroid cancer cells by targeting PKM2.

Although circular RNAs (circRNAs) are involved in cell proliferation, differentiation, apoptosis, and invasion, the underlying regulatory mechanisms of circRNAs in thyroid cancer have not been fully elucidated. This article aimed to study the role of circRNA regulated by N6-methyladenosine modification in papillary thyroid cancer (PTC). Quantitative real-time PCR, western blotting, and immunohistochemistry were used to investigate the expressions of circRNA nuclear receptor-interacting protein 1 (circNRIP1) in PTC tissues and adjacent noncancerous thyroid tissues. In vitro and in vivo assays were carried out to assess the effects of circNRIP1 on PTC glycolysis and growth. The N6-methyladenosine mechanisms of circNRIP1 were evaluated by methylated RNA immunoprecipitation sequencing, luciferase reporter gene, and RNA stability assays. Results showed that circNRIP1 levels were significantly upregulated in PTC tissues. Furthermore, elevated circNRIP1 levels in PTC patients were correlated with high tumor lymph node metastasis stage and larger tumor sizes. Functionally, circNRIP1 significantly promoted glycolysis, PTC cell proliferation in vitro, and tumorigenesis in vivo. Mechanistically, circNRIP1 acted as a sponge for microRNA (miR)-541-5p and miR-3064-5p and jointly upregulated pyruvate kinase M2 (PKM2) expression. Knockdown of m6 A demethylase α-ketoglutarate-dependent dioxygenase alkB homolog 5 (ALKBH5) significantly enhanced circNRIP1 m6 A modification and upregulated its expression. These results show that ALKBH5 knockdown upregulates circNRIP1, thus promoting glycolysis in PTC cells. Therefore, circNRIP1 can be a prognostic biomarker and therapeutic target for PTC by acting as a sponge for oncogenic miR-541-5p and miR-3064-5p to upregulate PKM2 expression.

Meta-analysis of the efficacy and safety of thermal ablation for treating large benign thyroid nodules.

OBJECTIVE: Many large benign thyroid nodules have symptoms and cosmetic problems. This study consisted of a meta-analysis to accurately assess the effect of thermal ablation on these nodules. METHODS: The PubMed, Embase, Web of Science, and Scopus databases were systematically searched for retrospective or prospective studies of thermal ablation since June 1, 2021. The weighted mean differences of the measures were analysed before and after treatment. RESULTS: A total of 10 eligible studies were included. By comparing the initial nodule volume with the nodular volume after thermal ablation, we found that the volume reduction rate was increased significantly after 1 month (SMD = 0.453, 95% CI: 0.323-0.583, p < .001), 3 months (SMD = 0.655, 95% CI: 0.563-0.747, p < .001), 6 months (SMD = 0.691, 95% CI: 0.607-0.774, p < .001), and 12 months (SMD = 0.694, 95% CI: 0.583-0.803), p < .001). The nodular volume was also found to decrease significantly, after 1 month (SMD = 2.381, 95% CI: 1.278-3.485, p < .001), 3 months (SMD = 5.071, 95% CI: 2.386-7.756, p < .001), 6 months (SMD = 5.363, 95% CI: 2.765-7.962, p < .001), and 12 months (SMD = 8.194, 95% CI: 2.113-14.274), p < .001). Symptom score (SMD = 4.419, 95% CI: 2.573-6.265, p < .001)and cosmetic score (SMD = 4.245, 95% CI: 2.566-5.359, p < .001) were reduced after thermal ablation. CONCLUSIONS: Thermal ablation could become an alternative to manage large benign thyroid nodules.

Incidental T1 stage medullary thyroid carcinoma: The effect of tumour diameter on prognosis and therapeutic implications.

OBJECTIVE: The definition of the tumour diameter of micro-medullary thyroid carcinoma (micro-MTC) is insufficient. It is controversial to perform a completion thyroidectomy immediately for incidental T1 stage MTC. DESIGN: We used the Surveillance, Epidemiology and End Results (SEER) registry to retrospectively analyze all patients with T1 stage MTC diagnosed between 2004 and 2015. The tumour diameter 1.0 and 0.5 cm were used as the cut-off points to group and analyze the differences of clinicopathological features. We analyzed the prognosis of patients with less than total thyroidectomy. METHODS: The disease-specific survival was the main outcome. Survival was estimated with Kaplan-Meier curves and Cox regression models estimated hazard ratios for tumour characteristics. RESULTS: A total of 908 patients diagnosed with T1 stage MTC in the SEER database were included. Our study found that tumour diameter 1.0 cm is a key point affecting the prognosis of T1 stage MTC patients, although patients with tumour diameter ≤ 0.5 cm had a lower rate of lymph node metastasis and no distant metastasis. Cox proportional hazard multivariate analysis showed that distant metastasis was the only risk factor for survival in patients with T1 stage MTC. Kaplan-Meier survival analysis showed that, regardless of tumour diameter, there was no significant difference between less than total thyroidectomy and total thyroidectomy in T1 stage patients. CONCLUSIONS: For incidental MTC with tumour diameter ≤ 1.0 cm and without distant metastasis, if there is no significant increase in serum calcitonin level after surgery and ret proto-oncogene (RET) gene mutation is negative, it may be not necessary to perform completion thyroidectomy immediately.

Clinicopathological Characteristics and Prognosis of Poorly Differentiated Thyroid Carcinoma Diagnosed According to the Turin Criteria.

OBJECTIVE: Poorly differentiated thyroid carcinoma (PDTC) is the primary cause of death in patients with nonanaplastic follicular cell-derived thyroid carcinoma. We purposed to identify the clinical and pathological characteristics of PDTC and their relationship with prognosis. METHODS: A retrospective analysis was conducted on patients diagnosed with PDTC at our institution from 2010 to 2018. All of their histopathology slides were reviewed by 2 experienced pathologists based on the Turin criteria. Furthermore, information regarding clinical characteristics, pathological characteristics, treatment strategy, and follow-up events were collected. The Kaplan-Meier method was used for survival analysis, while the log-rank test was used to compare survival curves. Then, the Cox proportional hazards model was used to perform univariate and multivariate analyses. RESULTS: Twenty-six patients with PDTC who met the Turin criteria were enrolled in this study. The median follow-up period of the included 26 patients was 76 months, while the 3- and 5-year survival rates were 40% and 18%, respectively. Notably, univariate analysis revealed that tumor size >4 cm (P = .038), extrathyroidal extension (ETE) (P = .020), distant metastases (P = .047), poorly differentiated areas >60% (P = .049), and Ki-67 labeling index >30% (P = .040) were associated with poor prognosis. On the other hand, multivariate analysis identified ETE (P = .007) and distant metastases (P = .031) as independent risk factors for poor prognosis. CONCLUSION: PDTC is a rare carcinoma with high invasiveness and poor prognosis. Patients with ETE or distant metastases may have adverse outcomes.

Unilateral Tnm T1 And T2 Papillary Thyroid Carcinoma With Lateral Cervical Lymph Node Metastasis: Total Thyroidectomy or Lobectomy?

OBJECTIVE: The aim of this study was to explore the effect of total thyroidectomy (TT) and lobectomy (LT) on the prognosis of unilateral papillary thyroid carcinoma (PTC) with lateral cervical lymph node metastasis. METHODS: Patients with PTC and lateral cervical lymph node metastasis who underwent lateral cervical lymph node dissection between January 2007 and December 2016 were retrospectively reviewed. To investigate the effect of surgical procedure on the prognosis of lymph node metastasis patients, other high-risk factors such as extrathyroidal invasion and large tumor size were excluded. All patients were in Tumor-Node-Metastasis (TNM) stage T1 and T2. Primary end point was recurrence-free survival (RFS). RESULTS: Among 264 PTC patients, 104 (39.4%) patients received TT and 160 (60.6%) patients received LT. With a median follow-up of 50 months (interquartile range, 34 to 74 months), 7 patients (2.65%) experienced recurrence. The 5-year RFS in the TT and LT groups was 96.1% and 97.7%, respectively, and was not significantly different (P = .765). Similar results were found when excluding patients who received radioiodine ablation, which were 97.7% and 97.4%, respectively (P = .752). Age ≥55 years (hazard ratio, 7.368; P = .018) and multifocality in the ispi-lateral lobe (hazard ratio, 10.059; P =.006) were identified as independent risk factors of recurrence. CONCLUSION: For unilateral TNM T1 and T2 PTC patients with lateral lymph node metastasis, there was no significant difference in the effect of TT and LT for RFS in the absence of other risk factors during the follow-up period. Patient age ≥55 years with multifocality in the unilateral lobe might be independent risk factors for prognosis.

Comparison of Outcomes Following Thyroid Isthmusectomy, Unilateral Thyroid Lobectomy, and Total Thyroidectomy in Patients with Papillary Thyroid Microcarcinoma of the Thyroid Isthmus: A Retrospective Study at a Single Center.

BACKGROUND Papillary thyroid microcarcinoma (PTMC) measures less than 10 mm in diameter, is more common in the thyroid lobes, but rarely presents in the thyroid isthmus. This retrospective study aimed to compare patient outcomes following various types of surgery in patients with PTMC of the thyroid isthmus, at a single center in China. MATERIAL AND METHODS We analyzed the clinical data of patients with isthmus thyroid cancer treated at the First Hospital of China Medical University. Patients were divided into 2 groups according to the tumor diameter-PTMC of the thyroid isthmus and papillary thyroid carcinoma >10 mm. The clinicopathological features between the 2 groups were compared, and the effects of various surgical methods on the prognosis of patients were analyzed. RESULTS A total of 70 patients were included in this study: 29 with PTMC of the thyroid isthmus (41.4%) and 41 with papillary thyroid carcinoma >10 mm (58.6%). The rates of lymph node metastasis (10.3% vs. 34.1%) and extrathyroid extension (0% vs. 14.6%) in the PTMC of the thyroid isthmus were significantly lower than those in the papillary thyroid carcinoma >10 mm. The recurrence-free survival (RFS) rate was 97.1%. Survival analysis showed that there was no significant difference in RFS among patients with PTMC of the thyroid isthmus undergoing isthmusectomy, unilateral lobectomy, and total thyroidectomy. CONCLUSIONS These findings from a single center showed that for patients with PTMC of the thyroid isthmus, who had no comorbidities, there was no significant difference in outcome between the 3 types of thyroid surgery.

Identification of a Novel Cuproptosis-Related Gene Signature and Integrative Analyses in Thyroid Cancer.

Cuproptosis is a novel programmed cell death that depends on copper. The role and potential mechanism of cuproptosis-related genes (CRGs) in thyroid cancer (THCA) are still unclear. In our study, we randomly divided THCA patients from the TCGA database into a training set and a testing set. A cuproptosis-related signature consisting of six genes (SLC31A1, LIAS, DLD, MTF1, CDKN2A, and GCSH) was constructed using the training set to predict the prognosis of THCA and was verified with the testing set. All patients were classified into low- and high-risk groups according to risk score. Patients in the high-risk group had a poorer overall survival (OS) than those in the low-risk group. The area under the curve (AUC) values for 5 years, 8 years, and 10 years were 0.845, 0.885, and 0.898, respectively. The tumor immune cell infiltration and immune status were significantly higher in the low-risk group, which indicated a better response to immune checkpoint inhibitors (ICIs). The expression of six cuproptosis-related genes in our prognostic signature were verified by qRT-PCR in our THCA tissues, and the results were consistent with TCGA database. In summary, our cuproptosis-related risk signature has a good predictive ability regarding the prognosis of THCA patients. Targeting cuproptosis may be a better alternative for THCA patients.

RBM47/SNHG5/FOXO3 axis activates autophagy and inhibits cell proliferation in papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the main type of thyroid carcinoma. Despite the good prognosis, some PTC patients may deteriorate into more aggressive diseases, leading to poor survival. Molecular technology has been increasingly used in the diagnosis and treatment of thyroid carcinoma. In this study, we identified that RNA Binding Motif Protein 47 (RBM47) was downregulated in PTC tissues and cells, and overexpression of RBM47 could activate autophagy and inhibit proliferation in PTC cells. RBM47 promotes but can not bind directly to Forkhead Box O3 (FOXO3). FOXO3 activates Autophagy Related Gene 3 (ATG3), ATG5, and RBM47 to form a loop and promote autophagy. RBM47 can bind directly to and stabilized lncRNA Small Nucleolar RNA Host Gene 5 (SNHG5) to inhibit PTC cells proliferation and activate autophagy in vitro and in vivo. SNHG5 inhibits ubiquitination and degradation of FOXO3 by recruiting Ubiquitin Specific Peptidase 21 (USP21), then promotes the translocation of FOXO3 from cytoplasm to nucleus. Our study revealed the regulatory mechanism of RBM47/SNHG5/FOXO3 axis on cell proliferation and autophagy in PTC, which may provide valuable insight for the treatment of PTC.

Different types of diabetes mellitus and risk of thyroid cancer: A meta-analysis of cohort studies.

Objective: Sex-specific thyroid cancer risk exists in patients diagnosed with diabetes mellitus (DM). However, thyroid cancer risk in different types of DM is still unclear. This meta-analysis aims to identify the real correlation between different types of DM and thyroid cancer risk in both sexes. Methods: Studies were identified by an electronic search of PubMed, EMBASE, and Cochrane Library on 16 January 2022. A random-effects model was used to estimate the relative risks (RRs). The Cochran's Q and I2 statistics were computed to detect heterogeneity between studies. Results: In comparison with non-DM counterparts, patients with DM had a 1.32-fold higher risk of thyroid cancer (95% CI, 1.22-1.44) with 1.26-fold (95% CI, 1.12-1.41) in men and 1.36-fold (95% CI, 1.22-1.52) in women, respectively. Subgroup analysis by the type of DM showed that the RR of thyroid cancer in patients with type 2 diabetes was 1.34 (95% CI, 1.17-1.53) in the study population with 1.32 (95% CI, 1.12-1.54) in men and 1.37 (95% CI, 1.12-1.68) in women, respectively; the RR of thyroid cancer was 1.30 (95% CI, 1.17-1.43) in patients with gestational diabetes; the risk of thyroid cancer in patients with type 1 diabetes was 1.51-fold in women but not in men. Although there were some heterogeneities, it did not affect the above results of this study. Conclusion: This study indicates that, compared with non-DM individuals, patients with any type of DM have an elevated thyroid cancer risk. This positive correlation between type 2 diabetes and thyroid cancer risk exists in both men and women. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/, CRD42022304028.

Prognostic Factors for Excellent Response to Initial Therapy in Patients With Papillary Thyroid Cancer From a Prospective Multicenter Study.

Prognostic factors for excellent response (ER) to initial therapy in patients with papillary thyroid cancer (PTC) have not been determined. In this study, we investigated the response to initial therapy in PTC patients and independent prognostic factors for ER in a prospective multicenter study in China. A total of 506 PTC patients from nine centers in China were enrolled in this study, all of whom underwent total or near total thyroidectomy with lymph node dissection and subsequent radioiodine therapy. Univariate and multivariable logistic regression analyses were carried out to determine the independent prognostic factors for ER. The optimal cutoff value of the number of metastatic lymph nodes for predicting ER was determined by the receiver operating characteristic curve. A total of 139 patients (27.5%) achieved ER after initial therapy. Extrathyroidal extension, the number of metastatic lymph nodes, and preablative-stimulated thyroglobulin (Ps-Tg) were independent risk factors for ER for the entire population. In a subgroup analysis, extrathyroidal extension and Ps-Tg were independent risk factors for ER in pathological N1a patients, while the number of metastatic lymph nodes and Ps-Tg were independent risk factors for ER in pathological N1b patients. The appropriate cutoff values of the number of metastatic lymph nodes in predicting ER were 5 and 13 for the entire population and pathological N1b PTC patients, respectively. PTC patients with more metastatic lymph nodes were more likely to fail to achieve ER. Extrathyroidal extension, the number of metastatic lymph nodes, and Ps-Tg were important prognostic factors for ER after initial therapy in PTC patients.

FTO suppresses glycolysis and growth of papillary thyroid cancer via decreasing stability of APOE mRNA in an N6-methyladenosine-dependent manner.

BACKGROUND: N6-methyladenosine (m6A) modification is the most common chemical modification in mammalian mRNAs, and it plays important roles by regulating several cellular processes. Previous studies report that m6A is implicated in modulating tumorigenesis and progression. However, dysregulation of m6A modification and effect of m6A demethylase fat-mass and obesity-associated protein (FTO) on glucose metabolism has not been fully elucidated in papillary thyroid cancer (PTC). METHODS: Quantitative real-time PCR (qRT-PCR), western blotting and immunohistochemistry were performed to explore the expression profile of FTO in PTC tissues and adjacent non-cancerous thyroid tissues. Effects of FTO on PTC glycolysis and growth were investigated through in vitro and in vivo experiments. Mechanism of FTO-mediated m6A modification was explored through transcriptome-sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), MeRIP-qPCR, luciferase reporter assays, RNA stability assay and RNA immunoprecipitation assay. RESULTS: FTO expression was significantly downregulated in PTC tissues. Functional analysis showed that FTO inhibited PTC glycolysis and growth. Further analyses were conducted to explore FTO-mediated m6A modification profile in PTC cells and Apolipoprotein E (APOE) was identified as the target gene for FTO-mediated m6A modification using RNA-seq and MeRIP-seq. FTO knockdown significantly increased APOE mRNA m6A modification and upregulated its expression. FTO-mediated m6A modification of APOE mRNA was recognized and stabilized by the m6A reader IGF2BP2. The findings showed that APOE also promoted tumor growth through glycolysis in PTC. Analysis showed that FTO/APOE axis inhibits PTC glycolysis by modulating IL-6/JAK2/STAT3 signaling pathway. CONCLUSION: FTO acts as a tumor suppressor to inhibit tumor glycolysis in PTC. The findings of the current study showed that FTO inhibited expression of APOE through IGF2BP2-mediated m6A modification and may inhibit glycolytic metabolism in PTC by modulating IL-6/JAK2/STAT3 signaling pathway, thus abrogating tumor growth.

Circular RNAs Regulate Glucose Metabolism in Cancer Cells.

Circular RNAs (circRNAs) were originally thought to result from RNA splicing errors. However, it has been shown that circRNAs can regulate cancer onset and progression in various ways. They can regulate cancer cell proliferation, differentiation, invasion, and metastasis. Moreover, they modulate glucose metabolism in cancer cells through different mechanisms such as directly regulating glycolytic enzymes and glucose transporter (GLUT) or indirectly regulating signal transduction pathways. In this review, we elucidate on the role of circRNAs in regulating glucose metabolism in cancer cells, which partly explains the pathogenesis of malignant tumors, and provides new therapeutic targets or new diagnostic and prognostic markers for human cancers.

Expression Profiles of Circular RNAs in Human Papillary Thyroid Carcinoma Based on RNA Deep Sequencing.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most prevalent type of thyroid cancer. Herein, we purposed to explore the expression patterns of circRNAs in PTC with the overarching goal of improving early diagnosis rates for individuals with PTC. METHODS: We used RNA deep sequencing to determine the expression patterns of circRNAs in PTC. Besides, RT-qPCR was employed to confirm circRNAs. The diagnostic potential of the circRNAs was explored by constructing ROC curves. GO along with KEGG pathway analyses were utilized to elucidate the potential biological roles of differentially expressed circRNAs. Moreover, we predicted cross talks among circRNAs, miRNAs, and mRNAs, followed by establishment of a ceRNA network. RESULTS: Deep sequencing of four PTC pairs and neighboring nontumor tissues identified 16569 circRNAs, of which, 301 were upregulated and 419 were downregulated. The RT-qPCR data demonstrated that the expression of chr5: 38481299-38530666-, chr2: 159932176-159945082-, chr10: 179994-249088+, chr3: 121378716-121381532+, and chr1: 237423092-237445522+ was downregulated, while the expression of chr4: 25665378-25667298+, chr5: 161330883-161336769-, chr1: 12578718-12579412-, chr7: 116695750-116700284+, and chr7: 116699071-116700284+ was upregulated. The stability test exhibited that circRNAs were more tolerant to temperature, RNase R, and time. On the other hand, ROC curves illustrated that chr4: 25665378-25667298+, chr1: 12578718-12579412-, chr7: 116699071-116700284+, chr7: 116695750-116700284+, chr5: 161330883-161336769-, and chr10: 179994-249088+ were effective as diagnostic indicators. However, a logistic regression model combining the six indicators achieved a better combined prediction index, with 97.7% sensitivity and 95.3% specificity. Moreover, GO along with KEGG pathway analyses illustrated that differentially expressed circRNAs were linked to tumorigenesis. Furthermore, bioinformatics analyses established a promising ceRNAs network among mRNAs, circRNAs, and miRNAs. CONCLUSION: Herein, we demonstrated that several circRNAs are promising PTC diagnostic biomarkers. Further study on the functions and mechanisms of these circRNAs may contribute to the understanding of PTC.

High Incidence of Distant Metastasis Is Associated With Histopathological Subtype of Pediatric Papillary Thyroid Cancer - a Retrospective Analysis Based on SEER.

Objective: Children with papillary thyroid cancer (PTC) have a higher invasive rate and distant metastasis rate, but the mortality rate is lower with unknown reasons. The majority of PTC cases comprise classical papillary thyroid carcinoma (CPTC) and follicular variant papillary thyroid carcinoma (FVPTC). This study aimed to determine the relationship between histopathological subtype and rate of distant metastasis and investigate factors influencing distant metastasis in pediatric PTC. Methods: A total of 102,981 PTC patients were recruited from SEER registry, 2004-2015. Proportion of distant metastasis between children (≤18 years) and adults with different histopathological subtypes was compared by propensity score matching. The cut-off age for distant metastasis in children was calculated by receiver operating characteristic (ROC) curve, and the risk factors for distant metastasis in pediatric patients were analyzed by logistic regression models. Results: Among the 1,484 children and 101,497 adults included in the study, the incidence of CPTC patients with distant metastasis in children was higher than that in adults (p<0.001). The ROC curve was calculated, which yielded a cut-off age for distant metastasis in CPTC children as 16 years old. In CPTC, the proportion of young children (2-16 years) with distant metastasis was higher than that of adolescents (17-18 years) and adults (>18 years) (both p<0.001). While there was no such trend in FVPTC. In young children (2-16 years), the incidence of CPTC with distant metastasis was higher than FVPTC (p=0.006). There was no difference between the proportion of CPTC and FVPTC with distant metastasis in adolescents (17-18 years) and adults. Logistic regression models revealed that extrathyroidal extension, lymph node metastasis and CPTC histopathological subtype were risk factors for distant metastasis in young children aged 2 -16 years. Conclusions: In CPTC, the incidence of distant metastasis in young children (2-16 years) was significantly higher than that in adolescents (17-18 years) and adults (>18 years). In patients with distant metastasis aged 2-16 years, the proportion of CPTC was higer than that of FVPTC. Extrathyroidal extension, lymph node metastasis, and CPTC histopathological subtype were risk factors for distant metastasis in young children aged 2-16 years.

Analysis of the strategy of LT4 prescribing and TSH monitoring for thyroid carcinoma after lobectomy.

BACKGROUND: Thyrotropin (TSH) suppression is a critical step in the management of differentiated thyroid carcinoma (DTC). The objectives of this study were to evaluate changes in TSH levels and a strategy of initial levothyroxine (LT4) supplementation for TSH suppression in low-risk differentiated thyroid carcinoma (lr-DTC) patients after lobectomy. METHODS: One hundred and ten patients with lr-DTC who received lobectomy were enrolled. Each of the patients was given 50 µg LT4 immediately after lobectomy and were retrospectively analyzed to evaluate the initial dose of LT4 suppression during the first year of follow-up. Risk factors influencing the TSH trend were also evaluated. RESULTS: Median TSH levels decreased significantly after lobectomy and the initiation of LT4 suppression and were stable from 3 to 12 months. Three months after lobectomy, 44.9% of patients fell into the newly recommended first TSH goal (0.35 to 2.0 mIU/L). Insufficient suppression (≥2.0 mIU/L) and oversuppression (<0.35 mIU/L) was observed in 9.4% and 45.8% of the patients, respectively. Preoperative TSH ≥2.0 mIU/L and the coexistence of Hashimoto thyroiditis (HT) were risk factors influencing the TSH trend. CONCLUSIONS: The monitoring of TSH could start from 3 months after lobectomy. An initial dose (50 µg) of LT4 could be adequate for initial suppression therapy in most patients. However, individual adjustment of the first dose may be necessary based on preoperative TSH concentration and the presence of HT.