Mechanism of DAPK1 for Regulating Cancer Stem Cells in Thyroid Cancer.

Death-associated protein kinase 1 (DAPK1) is a calcium/calmodulin (Ca2+/CaM)-dependent serine/threonine (Ser/Thr) protein kinase and is characteristically downregulated in metastatic cancer. Several studies showed that DAPK1 is involved in both the early and late stages of cancer. DAPK1 downregulation is elaborately controlled by epigenetic, transcriptional, posttranscriptional, and posttranslational processes. DAPK1 is known to regulate not only cancer cells but also stromal cells. Recent studies showed that DAPK1 was involved not only in tumor suppression but also in epithelial-mesenchymal transition (EMT) and cancer stem cell (CSC) formation in colon and thyroid cancers. CSCs are major factors in determining cancer aggressiveness in cancer metastasis and treatment prognosis by influencing EMT. However, the molecular mechanism involved in the regulation of cancer cells by DAPK1 remains unclear. In particular, little is known about the existence of CSCs and how they are regulated in papillary thyroid carcinoma (PTC) among thyroid cancers. In this review, we describe the molecular mechanism of CSC regulation by DAPK1 in PTC progression.

Interaction of BANCR in the relationship between Hashimoto's thyroiditis and papillary thyroid carcinoma expression patterns and possible molecular mechanisms.

BACKGROUND: Previous studies have established a connection between Hashimoto's thyroiditis (HT) and an increased risk of papillary thyroid carcinoma (PTC). However, the molecular mechanisms driving this association are not well understood. The long non-coding RNA (lncRNA) BRAF-activated non-coding RNA (BANCR) has been implicated in various cancers, suggesting a potential role in the HT-PTC linkage. METHODS: This study investigated the expression levels of BANCR in PTC and HT samples, compared to control tissues. We also examined the association between BANCR expression and clinicopathological features, including lymph node metastasis. Furthermore, we explored the molecular mechanisms of BANCR in PTC pathogenesis and its potential as a therapeutic target. RESULTS: BANCR expression was significantly lower in PTC samples than in controls, while it was moderately increased in HT samples. In PTC cases with concurrent HT, BANCR expression was markedly reduced compared to normal tissues. Our analysis revealed BANCR's role as an oncogene in PTC, influencing various cancer-related signaling pathways. Interestingly, no significant correlation was found between BANCR expression and lymph node metastasis. CONCLUSION: Our findings underscore the involvement of BANCR in the connection between HT and PTC. The distinct expression patterns of BANCR in PTC and HT, especially in PTC with concurrent HT, provide new insights into the molecular interplay between these conditions. This study opens avenues for the development of innovative diagnostic and therapeutic strategies targeting BANCR in PTC and HT.

Impact of radioiodine therapy on recurrence and survival outcomes in intermediate-risk papillary thyroid carcinoma -A systematic review and meta-analysis.

OBJECTIVE: The utility of radioiodine (RAI) therapy in intermediate-risk papillary thyroid carcinoma (PTC) remains a topic of ongoing discussion. This systematic review and meta-analysis aimed to consolidate existing evidence on the impact of postoperative RAI therapy on recurrence and survival outcomes in intermediate-risk PTC. METHODS: A literature search was performed using relevant keywords in PubMed, Scopus, and EMBASE. Articles from January 2008 to March 2023 were included. Odds ratios (ORs) and hazard ratios (HRs) were extracted from the individual articles, and pooled estimates were generated using meta-analysis. RESULTS: Eleven articles comprising 56,266 intermediate-risk PTC patients were included. 41,530 (73.8%) patients underwent postoperative RAI therapy, while 14,736 (26.2%) patients were kept on no-RAI (NOI) follow-up. No significant reduction in rates of structural disease recurrence was noted with RAI therapy in comparison to NOI follow-up (pooled univariate OR, 0.73, 95% confidence interval [CI], 0.29-1.87, I2 = 75%). RAI therapy was not a significant predictor of better recurrence-free survival (pooled multivariate HR, 0.21; 95% CI, 0.01-3.74, I2 = 94%). Interestingly, RAI therapy was associated with an overall survival benefit compared to NOI follow-up (pooled multivariate HR, 0.63; 95% CI, 0.48-0.82, I2 = 79%). CONCLUSIONS: This meta-analysis did not establish a conclusive benefit of RAI therapy in preventing structural disease recurrence or improving recurrence-free survival in intermediate-risk PTC. However, these results need to be interpreted with caution owing to significant heterogeneity in the existing literature. A prospective, randomised clinical trial is the need of the hour to better understand the effect of RAI therapy on long-term outcomes.

Hypoxic papillary thyroid carcinoma cells-secreted exosomes deliver miR-221-3p to normoxic tumor cells to elicit a pro-tumoral effect by regulating the ZFAND5.

Papillary thyroid cancer (PTC) has seen a worldwide expansion in incidence in the past three decades. Tumor-derived exosomes have been associated with the metastasis of cancer cells and are present within the local hypoxic tumor microenvironment, where they mediate intercellular communication by transferring molecules including microRNAs (miRNAs) between cells. Although miRNAs have been shown to serve as non-invasive biomarkers for cancer diagnosis, the role of hypoxia-induced tumor-derived exosomes in PTC progression remains unclear. Herein, we investigated the differentially expressed miRNA expression profiles from GEO datasets (GSE191117 and GSE151180) by using the DESeq package in R and identified a novel role for miR-221-3p as an oncogene in PTC development. In vivo and in vitro loss and gain assays were used to clarify the mechanism of hypoxic PTC cells derived exosomal-miR-221-3p in PTC. miR-221-3p was upregulated in human PTC plasma exosomes, tissues and cell lines. We found that hypoxic PTC cells derived exosomal-miR-221-3p promoted normoxic PTC cells proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) in vitro, while inhibition of miR-221-3p limited PTC tumor growth in our PTC xenograft model in nude mice. We finally identified ZFAND5, to be a miR-221-3p target. Mechanistically, hypoxic PTC cell lines-derived exosomes carrying miR-221-3p promoted PTC tumorigenesis by regulating ZFAND5. Our findings further the understanding of the underlying mechanisms associated with PTC progression and identify exosomal-miR-221-3p as a potential biomarker for the diagnosis and prognosis of PTC patients. Our study also suggests that miR-221-3p inhibitors could be a potential treatment strategy for PTC.

Novel LncRNA AK023507 inhibits cell metastasis and proliferation in Papillary Thyroid Cancer through ß-catenin/Wnt Signaling Pathway.

INTRODUCTION: Papillary Thyroid Cancer (PTC) represents a commonly encountered type of thyroid malignancy whose occurrence and development is influenced by long non-coding RNA (LncRNA). A novel lncRNA (LncRNA AK023507), known to have tumor suppressive functions, was shown to prevent breast cancer cells from proliferating and metastasizing, but its mechanism in PTC is unclear. METHODS: Using PTC tissues and cell lines, the expression of LncRNA AK023507 was investigated by quantitative Real-time Polymerase Chain Reaction (qRT-PCR). The effects of knockdown or overexpression of LncRNA AK023507 on cell growth and movement were investigated through various cell experiments in vitro. The presence of important functional proteins was determined by Western blotting, with the recovery experiment used for verification. RESULTS: LncRNA AK023507 was found to have low expression in both the PTC cell lines and tissue samples. Knockdown of LncRNA AK023507 in PTC cells significantly promoted cell proliferation, migration, and invasion, while overexpression of LncRNA AK023507 resulted in the opposite effects. Furthermore, LncRNA AK023507 could regulate the expression of ß-catenin/Wnt signaling pathway as confirmed by recovery experiment. CONCLUSION: By acting through the ß-catenin/Wnt signaling pathway, LncRNA AK023507 prevented PTC cells from proliferating and metastasizing. These novel findings indicate that LncRNA AK023507 could be of prognostic and diagnostic value as a potential biomarker of PTC.

NTRK Fusion in a Cohort of BRAF p. V600E Wild-Type Papillary Thyroid Carcinomas.

Owing to the availability of a potent tropomyosin receptor kinase (TRK) inhibitor, it is necessary to develop an effective strategy to identify an enriched population of NTRK fusions in papillary thyroid carcinoma (PTC) in routine diagnostic practice. The reported prevalence of NTRK fusion in a large cohort of PTC is ∼3%. We performed an analysis to refine the characteristic histologic features of PTCs harboring NTRK fusions and further validate the diagnostic utility of pan-TRK immunohistochemistry as a screening tool. In this study, 450 PTCs known to harbor no BRAF p. V600E mutations were screened by pan-TRK immunohistochemistry, and the cases with TRK expression were confirmed by RNA-based next-generation sequencing assay. Eleven NTRK fusion cases were detected (2.4%), and all PTCs were classical subtypes. NTRK1 and NTRK3 were involved in the fusion with 9 different partner genes. Most cases showed similar characteristic histologic findings. Nodular permeative border, multinodular growth with a predominantly follicular pattern, extensive lymphatic invasion, and prominent internodular and intratumoral fibrosis were the characteristic histologic features of NTRK-rearranged PTCs. The ill-defined margins in the ultrasonography findings, which could not be clearly distinguished from the adjacent nontumorous thyroid tissue, were nodular permeative margins in histologic findings. Therefore, preoperative ultrasonographic findings in nodule margins were consistent with the final histologic findings. NTRK1/3 fusion in PTCs showed an overall sensitivity of 100% (95% CI, 71.51%-100%) and specificity of 100% (95% CI, 71.51%-100%) in the 22 cases examined, as confirmed with next-generation sequencing. Our study provides an integrative report of the preoperative ultrasonographic, histologic, immunohistochemical, and molecular features of NTRK-rearranged PTCs. Based on these findings, we propose an algorithmic approach for the stepwise assessment of NTRK fusions in PTCs.

Transcriptomic Analysis Reveals Dysregulation of the Mycobiome and Archaeome and Distinct Oncogenic Characteristics according to Subtype and Gender in Papillary Thyroid Carcinoma.

Papillary Thyroid Carcinoma (PTC) is characterized by unique tumor morphology, treatment response, and patient outcomes according to subtype and gender. While previous studies have implicated the intratumor bacterial microbiome in the incidence and progression of PTC, few studies have investigated the potential role of fungal and archaeal species in oncogenesis. In this study, we aimed to characterize the intratumor mycobiome and archaeometry in PTC with respect to its three primary subtypes: Classical (CPTC), Follicular Variant (FVPTC), and Tall Cell (TCPTC), and also with respect to gender. RNA-sequencing data were downloaded from The Cancer Genome Atlas (TCGA), including 453 primary tumor tissue samples and 54 adjacent solid tissue normal samples. The PathoScope 2.0 framework was used to extract fungal and archaeal microbial read counts from raw RNA-sequencing data. Overall, we found that the intratumor mycobiome and archaeometry share significant similarities in CPTC, FVPTC, and TCPTC, although most dysregulated species in CPTC are underabundant compared to normal. Furthermore, differences between the mycobiome and archaeometry were more significant between males and females, with a disproportionate number of fungal species overabundant in female tumor samples. Additionally, the expression of oncogenic PTC pathways was distinct across CPTC, FVPTC, and TCPTC, indicating that these microbes may uniquely contribute to PTC pathogenesis in each subtype. Furthermore, differences in the expression of these pathways were observed between males and females. Finally, we found a specific panel of fungi to be dysregulated in BRAF V600E-positive tumors. This study demonstrates the potential importance of microbial species to PTC incidence and oncogenesis.

Novel Susceptibility Genes Drive Familial Non-Medullary Thyroid Cancer in a Large Consanguineous Kindred.

Familial non-medullary thyroid cancer (FNMTC) is a well-differentiated thyroid cancer (DTC) of follicular cell origin in two or more first-degree relatives. Patients typically demonstrate an autosomal dominant inheritance pattern with incomplete penetrance. While known genes and chromosomal loci account for some FNMTC, the molecular basis for most FNMTC remains elusive. To identify the variation(s) causing FNMTC in an extended consanguineous family consisting of 16 papillary thyroid carcinoma (PTC) cases, we performed whole exome sequence (WES) analysis of six family patients. We demonstrated an association of ARHGEF28, FBXW10, and SLC47A1 genes with FNMTC. The variations in these genes may affect the structures of their encoded proteins and, thus, their function. The most promising causative gene is ARHGEF28, which has high expression in the thyroid, and its protein-protein interactions (PPIs) suggest predisposition of PTC through ARHGEF28-SQSTM1-TP53 or ARHGEF28-PTCSC2-FOXE1-TP53 associations. Using DNA from a patient's thyroid malignant tissue, we analyzed the possible cooperation of somatic variations with these genes. We revealed two somatic heterozygote variations in XRCC1 and HRAS genes known to implicate thyroid cancer. Thus, the predisposition by the germline variations and a second hit by somatic variations could lead to the progression to PTC.

Significance of interstitial fibrosis and p16 in papillary thyroid carcinoma.

We enrolled 264 patients with papillary thyroid carcinoma (PTC). We performed immunohistochemical detection of p16 and determined the degree of interstitial fibrosis (IF). The expression of p16 was associated with pathological tumor-node-metastasis (pTNM) stage and age (p < 0.05). The cancer-specific survival (CSS) was longer in p16-negative patients (195.73 vs. 181.78 months, p = 0.007). p16 was significantly related to the degree of IF (r = 0.130, p = 0.035). PTC patients with no or mild fibrosis tended to have a larger tumor (p = 0.045). The degree of fibrosis was related to the proportion of papillary structure components (p = 0.025). Univariate and multivariate survival analyses showed that relapse-free survival (RFS) was longer in patients with moderate/severe IF (p < 0.05). In summary, p16 was correlated with prognosis and IF of PTC. Patients with moderate/severe IF tend to have better prognosis in RFS.

Correlation between low expression of protein disulfide isomerase A3 and lymph node metastasis in papillary thyroid carcinoma and poor prognosis: a clinicopathological study of 1,139 cases with long-term follow-up.

The incidence of papillary thyroid carcinoma (PTC) is increasing worldwide. The biomarkers to identify aggressive types of PTC are limited, illustrating the need to establish reliable novel biomarkers. Protein disulfide isomerase A3 (PDIA3) is a chaperone protein that modulates the folding of newly synthesized glycoproteins and stress-responsive proteins in the endoplasmic reticulum. Although the role of PDIA3 in various cancers such as breast, uterine cervix, head and neck, and gastrointestinal tract has been examined, its expression in thyroid cancer has not been reported. We retrospectively reviewed accumulated data with long-term follow-up of 1,139 PTC patients, and investigated the correlation between immunohistochemical expression of PDIA3 in PTC patients and clinicopathological features and prognosis. PDIA3 expression was significantly lower in PTCs compared to normal thyroid tissues (NTT; n = 80, p = 0.002). In PTCs, correlation between low PDIA3 expression and lymph node metastasis (p = 0.018) and the number of positive nodes (p = 0.004) was observed. Patients with low PDIA3 expression exhibited worse cause-specific survival compared to those with high PDIA3 expression (p = 0.013). Our findings indicate that low PDIA3 expression is related to poor clinical outcome in PTC patients, and that PDIA3 may potentially be a novel ancillary biomarker. Further clarification of the biological role of PDIA3 in PTC is warranted for the future clinical application.

Clinical and prognosis value of the number of metastatic lymph nodes in patients with papillary thyroid carcinoma.

OBJECTIVE: It has been reported that papillary thyroid carcinoma (PTC) patients with lymph node metastasis (LNM) are largely associated with adverse outcomes. The present study aimed to assess the correlation between the number of metastatic lymph nodes (NMLNs) and clinical prognosis in patients with PTC. METHODS: We retrospectively reviewed the medical records of patients with PTC who underwent initial thyroid cancer surgery in Renmin Hospital of Wuhan University between 2017 and 2019. A total of 694 patients with PTC and cervical lymph node dissection as well as a total checked number of lymph nodes ≥ 5 were involved in this study. The clinicopathological characteristics of patients were compared according to NMLNs, the number of central cervical lymph nodes (CLNs) and the number of lateral lymph nodes (LLNs). RESULTS: NMLNs > 5, CLNs > 5 and LLNs > 5 were 222 (32.0%), 159 (24.3%) and 70 (10.1%) seen in the analyzed samples, respectively. Young patients, patients with larger tumor diameter, bilaterality, multifocality and gross extrathyroidal extension (ETE) were more inclined to NMLNs > 5, CLNs > 5 and LLNs > 5 (P < 0.05). It was found that the recurrence-free survival among pN1 patients was significantly discrepant between different groups (NMLNs ≤ 5/5: P = 0.001; LLNs ≤ 5/5: P < 0.001). In multivariate logistic regression analysis, patients aged < 55 years (OR = 1.917), primary tumor size > 10 mm (OR = 2.131), bilaterality (OR = 1.889) and tumor gross ETE (OR = 2.759) were independent predictors for high prevalence of total NMLNs > 5 (P < 0.05). Specially, patients aged < 55 years (OR = 2.864), primary tumor size > 10 mm (OR = 2.006), and tumor gross ETE (OR = 2.520) were independent predictors for high prevalence of CLNs > 5 (P < 0.01); Bilaterality (OR = 2.119), CLNs > 5 (OR = 6.733) and tumor gross ETE (OR = 4.737) were independent predictors for high prevalence of LLNs > 5 (P < 0.05). CONCLUSIONS: In conclusion, it is evident that NMLNs is related to the invasive clinicopathological features and adverse outcome of patients with PTC which should be correctly evaluated to provide an appropriate guidance for reasonable treatment and careful follow-up.

Long non-coding RNA AGAP2-AS1 promotes proliferation and metastasis in papillary thyroid cancer by miR-628-5p/KLF12 axis.

Long non-coding RNA (lncRNA) AGAP2-AS1 acts as an oncogene in several types of cancers. However, the role and mechanism of AGAP2-AS1 in papillary thyroid carcinoma (PTC) remain unclear. Thus, in this study, we aimed to explore the role of AGAP2-AS1 in PTC. Our results showed that AGAP2-AS1 was significantly upregulated in PTC tissues. Knockdown of AGAP2-AS1 inhibited the proliferation, migration and invasion of PTC cells. In vivo experiment showed that AGAP2-AS1 knockdown inhibited the tumorigenesis of PTC. MiR-628-5p was found to act as a target miRNA of AGAP2-AS1 in PTC. The expression level of miR-628-5p in PTC tissues was negatively associated with that of AGAP2-AS1. Inhibition of miR-628-5p attenuated the effects of AGAP2-AS1 knockdown on PTC. Moreover, miR-628-5p directly bound to the 3'UTR of KLF12 and inhibited the expression of KLF12. Knockdown of KLF12 enhanced the inhibitory effects of miR-628-5p on PTC cell proliferation and metastasis. In conclusion, these findings indicated that AGAP2-AS1 exerted an oncogenic role in PTC progression and metastasis. The effects of AGAP2-AS1 might be mediated by the regulation of miR-628-5p/KLF12 axis.

BGL3 inhibits papillary thyroid carcinoma progression via regulating PTEN stability.

PURPOSE: BGL3, a novel long non-coding RNA (lncRNA) that plays a crucial role in several human malignancies. However, the clinical significance and biological function of BGL3 in papillary thyroid carcinoma (PTC) have not been explored. Herein, we aimed to investigate the role of BGL3 in human PTC. METHODS: A total of 85 pairs of PTC and normal tissues were collected for clinicopathological analysis. Expression of BGL3 was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The effects of BGL3 on PTC cells ware determined by CCK-8, colony formation, EdU and wound healing assays. The molecular mechanism underlying BGL3 was tested by ChIP, Co-IP, RNA pull-down and luciferase reporter assays. In vivo experiments were conducted using xenografts in nude mice. RESULTS: BGL3 was significantly decreased in PTC tissues compared to adjacent normal thyroid tissues, and it was transcriptionally repressed by oncogene Myc. Low BGL3 is positively related to larger tumor size, lymph node metastasis, later TNM stage and poor prognosis. Overexpression of BGL3 inhibited PTC cell proliferation and migration in vitro, and reduced tumor size and lung metastasis nodules in vivo. BGL3 was mainly located in the cytoplasm, in which interacted with PTEN and recruited OTUD3, enhancing the de-ubiquitination effect of OTUD3 on PTEN, resulting in increasing PTEN protein stability and inactivating carcinogenic PI3K/AKT signaling. CONCLUSIONS: Our data underscore the critical tumor-inhibiting role of BGL3 in PTC via post-translational regulation of PTEN protein stability, which may serve as a novel therapeutic target and prognostic biomarker in human PTC.

Circular RNA circ_0008274 enhances the malignant progression of papillary thyroid carcinoma via modulating solute carrier family 7 member 11 by sponging miR-154-3p.

CircRNAs have been implicated in the progression of human cancers, including papillary thyroid carcinoma (PTC). Although circ_0008274 has been demonstrated as a potential oncogenic circRNA in PTC, our understanding of its molecular determinants is limited. The levels of circ_0008274, miR-154-3p and solute carrier family 7 member 11 (SLC7A11) mRNA were determined by quantitative real-time polymerase chain reaction (qRT-PCR). SLC7A11 protein level was assessed by western blot. Cell apoptosis, migration, and adhesion capacities were examined by flow cytometry, transwell and cell adhesion assays, respectively. The targeted correlations among circ_0008274, miR-154-3p and SLC7A11 were confirmed by a dual-luciferase reporter assay. Animal studies were performed to observe the role of circ_0008274 in tumor growth in vivo. Our data showed that the high levels of circ_0008274 and SLC7A11 were associated with poor prognosis of PTC patients. The knockdown of circ_0008274 or SLC7A11 enhanced PTC cell apoptosis and repressed cell migration and adhesion in vitro. Circ_0008274 knockdown suppressed tumor growth in vivo. Mechanistically, circ_0008274 modulated SLC7A11 expression by acting as a sponge of miR-154-3p. SLC7A11 was a functional mediator of circ_0008274 in regulating PTC cell apoptosis, migration and adhesion in vitro, and miR-154-3p overexpression repressed PTC progression in vitro by targeting SLC7A11. Our findings identified that the knockdown of circ_0008274 repressed PTC malignant progression at least in part through regulating the miR-154-3p/SLC7A11 axis, providing a promising therapeutic opportunity for PTC treatment.

Risk factors for central lymph node metastasis in the cervical region in papillary thyroid carcinoma: a retrospective study.

BACKGROUND: To investigate the influence of different risk factors on central lymph node metastasis (CLNM) in the cervical region in patients with papillary thyroid carcinoma (PTC). METHODS: This retrospective study included 2586 PTC patients. Potential risk factors were identified by univariate analysis, and the relationships between these factors and CLNM were ascertained by multivariable analysis. A scoring system was constructed, and the optimal cut-off value was determined. RESULTS: On univariate analysis, sex, age, tumor diameter, multifocality, capsule invasion, vascular invasion, total number of lymph nodes in the central region, and serum thyroid peroxidase antibody (TPOAb) concentration were identified as potential risk factors for CLNM in the cervical region, whereas nerve invasion, thyroid-stimulating hormone concentration, and thyroglobulin antibody (TgAb) concentration were not. Multivariable analysis indicated that male sex, young age, large tumor diameter, multifocality, vascular invasion, a large number of central lymph nodes, and a low TPOAb concentration were significant risk factors. From these factors, a preoperative CLNM risk assessment scale was constructed for predicting CLNM in the cervical region for PTC patients. CONCLUSION: Male sex, young age, large tumor diameter, multifocality, vascular invasion, a large number of central lymph nodes, and a low TPOAb concentration were positively correlated with CLNM in the cervical region in PTC patients. The preoperative CLNM risk assessment scale based on these risk factors is expected to offer accurate preoperative assessment of central lymph node status in PTC patients.

Tripartite motif containing 14: An oncogene in papillary thyroid carcinoma.

Tripartite motif (TRIM)-containing protein 14 (TRIM14) is implicated in many malignancies. Presently, we studied whether TRIM14 played a role in human papillary thyroid carcinoma (PTC). Herein, TRIM14 was up-regulated in tumor tissues when compared with normal thyroid samples. Among PTC patients, enhanced TRIM14 predicted short recurrence free survival (RFS) time. Then, we found that knockdown of TRIM14 in human PTC K1 cells inhibited cell proliferation, induced cell apoptosis and prevented the tumorigenicity in nude mice. On the contrary, TRIM14 overexpression in human PTC TPC1 cells promoted cell proliferation while inhibited cell apoptosis. TRIM14 exerted its oncogenic activities via promoting the activation of signal transducer and activator of transcription 3 (STAT3). Further, TRIM14 interacted with the suppressor of cytokine-signaling-1 (SOCS1), a negative regulator of STAT3 activation, and knockdown of TRIM14 inhibited SOCS1 ubiquitination. In conclusion, TRIM14 may be a prognostic factor and oncogene in PTC, and may be a potential target for PTC intervention.

PTC located in the upper pole is more prone to lateral lymph node metastasis and skip metastasis.

BACKGROUND: Lateral lymph node metastasis (LLNM) is very common in papillary thyroid carcinoma (PTC). The influence of tumour location on LLNM remains controversial. The purpose of this study was to reveal the association between PTC tumours located in the upper pole and LLNM. METHODS: We reviewed a total of 1773 PTC patients who underwent total thyroidectomy with central and lateral lymph node dissection between 2013 and 2018. Patients were divided into two groups according to tumour location. Univariate and multivariate analyses were performed to identify risk factors associated with LLNM and "skip metastasis". RESULTS: In the upper pole group, LLNM and skip metastasis were significantly likely to occur. Multivariate analysis showed that tumours located in the upper pole, male sex, extrathyroidal extension (ETE), central lymph node metastasis (CLNM) and tumour size were independent risk factors for LLNM, with odds ratios ([ORs], 95% confidence intervals [CIs]) of 2.136 (1.707-2.672), 1.486 (1.184-1.867), 1.332 (1.031-1.72), 4.172 (3.279-5.308) and 2.496 (1.844-3.380), respectively. Skip metastasis was significantly associated with the primary tumour location in the upper pole and age > 55 years, with ORs of 4.295 (2.885-6.395) and 2.354 (1.522-3.640), respectively. CONCLUSIONS: In our opinion, papillary thyroid tumours located in the upper pole may have an exclusive drainage pathway to the lateral lymph nodes. When the tumour is located in the upper pole, lateral neck dissection should be evaluated meticulously.

A comparative study of two liquid-based preparation methods: membrane-based and sedimentation in fine needle aspiration cytology diagnosis in thyroid nodules.

BACKGROUND: As thyroid fine needle aspiration (FNA) shows a certain limitation in the diagnosis of conventional smears, novel approaches like liquid-based cytology (LBC) have been gradually applied recently. Studies have shown the difference between the conventional smears (CSs) and liquid-based smears on fine needle aspiration cytology (FNAC) diagnosis, but the impacts of different liquid-based preparation (LBP) methods, including membrane-based and sedimentation, on diagnosis are still not clear. In this study, the effects of liquid-based smears prepared by different methods on the cytological interpretation were studied. METHODS: A total of 221 thyroid liquid-based FNAC cases from January 2017 to October 2018 were collected. We retrospectively studied and compared the effects of the membrane-based and sedimentation LBP methods through The Bethesda System for Reporting Thyroid Cytopathology (TBS) diagnosis and risk of malignancy assessment. Besides, we made an evaluation on the diagnostic differences in the effects of different preparation methods on the cell morphology and tissue structure of papillary thyroid carcinoma (PTC) for more accurate FNAC diagnosis. RESULTS: Among the 221 cases reviewed, membrane-based method was applied in 153 cases and sedimentation in 68 cases. According to the diagnostic criteria of 2017 TBS, TBSVI and TBSV thyroid could be cytologically diagnosed by membrane-based (49.0% (75/153) and 25.5% (39/153)) and sedimentation (52.9(36/68) and 25(17/68)) methods, and both were confirmed as PTC through histopathological diagnosis after operation, with the malignancy degree as high as 100%. In addition, of the 30 cases that were diagnosed as TBSIII thyroid nodules with the membrane-based method, 15 cases were pathologically malignant after an operation, with the malignancy degree of 50% (15/30), while that in 11 cases using the sedimentation method was 45.4% (5/11). PTC could be detected in both the TBSIV and TBSII thyroid nodules diagnosed by membrane-based method, with the sensitivity of 87.0% (114/131) lower than that by sedimentation method (91.4% (53/58)), showing the lower consistency with the histopathological result (K = 0.635 vs K = 0.757). Among the membrane-based smears, 23.5% (36/153) had fewer follicular epithelial cells, 55.6% (20/36) of which were considered to be suspicious for PTC from cell karyotype and tissue arrangement. While among the sedimentation smears, 16.2% (11/68) had fewer follicular epithelial cells, and 63.6% (7/11) was suspicious for PTC. In 72.5% (95/131) membrane-based smears of PTC, the papillary and swirling structures were not obvious, showing as crowded syncytial cell masses, while in 55.2% (32/58) sedimentation smears, both structures were visible with obvious three-dimensional papillary structure, and the fibrovascular axis still remained. CONCLUSION: LBP technique is feasible for FNAC diagnosis, and the sedimentation shows more advantages, like higher PTC detection rate and good consistency with postoperative histopathological diagnosis. A clear understanding of the subtle differences in the effects of membrane-based and sedimentation methods on the cell morphology and tissue structure could be conducive to the definitive diagnosis of PTC before operation.

Long non-coding RNA LINC00152 promotes cell growth and invasion of papillary thyroid carcinoma by regulating the miR-497/BDNF axis.

Long intergenic non-coding RNA 152 (LINC00152) was reported to be tightly linked to tumorigenesis and progression in multiple cancers. However, its biological role and modulatory mechanism in papillary thyroid carcinoma (PTC) has not been elucidated. In this study, we determined the expression levels of LINC00152 in PTC tissues and cell lines by quantitative real time polymerase chain reaction (qRT-PCR). Cell proliferation, colony formation, migration, and invasion were measured by a Cell Counting Kit-8 assay, colony formation analysis, wound healing, and transwell invasion assay, respectively. A luciferase reporter assay and qRT-PCR were used to determine whether LINC00152 interacts with miR-497 directly. We established a xenograft mouse model to examine the underlying molecular mechanism and effect of LINC00152 on tumor growth in vivo. We found that LINC00152 expression was significantly increased in PTC tissues and derived cell lines. LINC00152 knockdown significantly inhibited proliferation, colony formation, migration, and invasion in vitro, and impaired tumor growth in vivo. We revealed that LINC00152 functioned as a competing endogenous RNA to the miR-497 sponge, downregulating its downstream target brain-derived neurotrophic factor (BDNF), which is an oncogene in thyroid cancer. These findings suggest that LINC00152 is responsible for PTC cell proliferation and invasion and exerts its function by regulating the miR-497/BDNF axis.

Prognostic value of a two-microRNA signature for papillary thyroid cancer and a bioinformatic analysis of their possible functions.

BACKGROUND: Recent scientific evidence has suggested that microRNAs (miRNAs) play an important role in papillary thyroid cancer (PTC). In the current study, we aim to identify a miRNA-related signature as the sensitive and novel prognostic biomarkers. METHODS: We performed a comprehensive analysis of the data downloaded from the Cancer Genome Atlas (TCGA) database. The association between survival outcome and miRNA was assessed by the univariate and multivariate Cox proportional hazards model. The risk score model was built to evaluate the predicting value of miRNA signature. The potential biofunctions and transcription factors of target miRNAs were investigated through bioinformatic analysis. The result was verified by the quantitative real-time polymerase chain reaction (qRT-PCR) in 32 pairs of PTC and adjacent nontumor tissues. In addition, the results were verified by other cohorts from gene expression omnibus (GEO) as detected by microarrays. RESULTS: A total of 1030 miRNAs were identified from the TCGA database. Thirty-six key intersection miRNAs were obtained. The associations between clinical features and key miRNAs were evaluated. Eventually, a two-miRNA signature (hsa-miR-181a-2-3p and hsa-miR-138-1-3p) was identified. The power of the miRNA prognostic signature was effective. In total, we identified 202 genes that were associated with 2 miRNAs above, and the top 10 enriched transcript factors that highly related with the target miRNAs were explored. The qRT-PCR and GEO data validation were consistent with bioinformatics results. CONCLUSIONS: A tumor-specific miRNA signature was identified, and the joint prognostic power was evaluated, which may be potential biomarkers for prognosis of PTC. IMPACT: The two-miRNA signature could become the potential prognostic indicator of PTC in the future.