Poor Prognosis In Papillary Thyroid Carcinoma Research Articles

BRAF-induced EHF expression affects TERT in aggressive papillary thyroid cancer.

BRAFV600E and TERT promoter mutations in papillary thyroid carcinoma (PTC) have a synergistic effect on prognosis. This effect is believed to arise from MAPK activation triggered by BRAFV600E, leading to the upregulation of ETS transcription factors that bind to the mutant TERT promoter. To explore the role of ETS factors in relation to clinical features, BRAFV600E and TERT promoter mutations in PTC. Transcriptomic data for 28 ETS factors were analyzed in the PTC cohort of The Cancer Genome Atlas (TCGA, n=399) and subsequently validated in a local cohort (n=93). In vitro experiments were performed to investigate the regulatory role in relation to BRAFV600E and TERT expression. TCGA identified ETS1, ERG, FLI1, GABPA, EHF, ETV6 and SPDEF as differentially expressed genes between stages I+II and III+IV. In both cohorts, EHF was consistently associated with adverse clinical features, BRAFV600E and TERT promoter mutation/expression. Notably, in BRAFV600E mutated PTC, high EHF expression was associated with shorter disease-free survival. Cases harboring concurrent BRAFV600E, TERT promoter mutations and high EHF expression exhibited the shortest disease-free survival. In cells harboring concurrent BRAFV600E and TERT promoter mutation, over-expression of EHF significantly increased TERT expression while knockdown or pharmacological inhibition of BRAF significantly decreased both EHF and TERT expression. In addition, ChIP-qPCR analysis suggested a potential binding of EHF in TERT promoter mutant cells but not in TERT promoter wild-type cells. The ETS transcription factor EHF is associated with poor prognosis in PTC. This is potentially mediated by BRAF-induced upregulation of EHF which in turn increases TERT expression in TERT promoter mutated cells.

Budding uninhibited by benzimidazoles 1 might be a poor prognosis biomarker promoting the progression of papillary thyroid cancer.

Papillary thyroid carcinoma (PTC) is one of the most widespread malignant tumors of the endocrine system, with a high incidence. Budding uninhibited by benzimidazoles 1 (BUB1), one of the spindle assembly checkpoint (SAC) genes, is a multitask protein kinase required for eukaryotic chromosome segregation. Although BUB1 has been explored in several types of cancer, its biological role and molecular mechanisms in PTC remain unclear. In this study, we performed an examination of four public datasets along with local PTC cohorts and discovered that BUB1 was elevated in PTC compared to non-cancer tissues. High BUB1 expression was linked with the status of BRAFV600E , RAS, and TERT after statistical analysis. Clinically, BUB1 is associated with a variety of clinicopathological features in PTC patients. Interestingly, analysis of the TCGA database showed that BUB1 was closely associated with poor prognosis of PTC and significantly correlated with PFS. As determined by regression analysis, BUB1, and T stage were independent predictors of PTC and were related to BRAFV600E and lymph node metastatic status. By RT-qPCR, BUB1 was considerably overexpressed in PTC cell lines in comparison with normal thyroid epithelial cells. We confirmed that the knockdown of BUB1 in BCPAP and TPC1 cell lines significantly inhibited cell proliferation, cloning, and migration in vitro experiments. These results imply that BUB1 may be a significant oncogenic gene that is directly associated with the prognosis of PTC and may represent a future target for therapeutic intervention.

METTL3 restrains papillary thyroid cancer progression via m6A/c-Rel/IL-8-mediated neutrophil infiltration

Growing evidence indicates that N6-methyladenosine (m6A) isthe most pervasive RNA modification in eukaryotic cells. However, the specific role of METTL3 in papillary thyroid carcinoma (PTC) initiation and development remains elusive. Here we found that downregulation of METTL3 was correlated with malignant progression and poor prognosis in PTC. A variety of gain- and loss-of-function studies clarified the effect of METTL3 on regulation of growth and metastasis of PTC cells invitro and invivo. By combining RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (meRIP-seq), our mechanistic studies pinpointed c-Rel and RelA as downstream m6A targets of METTL3. Disruption of METTL3 elicited secretion of interleukin-8 (IL-8), and elevated concentrations of IL-8 promoted recruitment of tumor-associated neutrophils (TANs) in chemotaxis assays and mouse models. Administration of the IL-8 antagonist SB225002 substantially retarded tumor growth and abolished TAN accumulation in immunodeficient mice. Our findings revealed that METTL3 played a pivotal tumor-suppressor role in PTC carcinogenesis through c-Rel and RelA inactivation of the nuclear factor κB (NF-κB) pathway by cooperating with YTHDF2 and altered TAN infiltration to regulate tumor growth, which extends our understanding of the relationship between m6A modification and plasticity of the tumor microenvironment.

PD-L1, PDK-1 and p-Akt are correlated in patients with papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma. To investigate the clinical significance of programmed death ligand 1 (PD-L1) and phosphoinositide-dependent protein kinase 1 (PDK1) in PTC. A total of 194 PTC patients were recruited. Contralateral normal thyroid tissues were obtained and used as controls (n = 80). The expression levels of PD-L1, PDK1 and p-Akt were determined using immunohistochemistry. The PD-L1, PDK1 and p-Akt were upregulated in cancer tissues compared to the normal tissues. The mean optical density (MOD) values of PD-L1, PDK1 and p-Akt were significantly higher in the PTC tissues. The expression of PD-L1 positively correlated with the levels of PDK1 and p-Akt. In addition, the expression of PD-L1, PDK1 and p-Akt in PTC patients without chronic lymphocytic thyroiditis (CLT) was significantly higher than the expression of those proteins in the CLT patients. The patients with higher expression levels of PD-L1, PDK1 or p-Akt had remarkably larger tumors and higher rates of TNM III-IV, capsular infiltration, lymph node metastasis, and of recurrence. The Kaplan-Meier curve showed that patients with lower expression of PD-L1, PDK1 or p-Akt had significantly longer recurrence-free time. The logistic regression analysis revealed that only CLT, PD-L and capsular infiltration were risk factors for patients' five-year recurrence. The PD-L1, PDK1 and p-Akt were found to be positively correlated with a poor prognosis in PTC.

Prognostic Signature: Immune Confrontation in the Papillary Thyroid Carcinoma Microenvironment

Background: Papillary thyroid carcinoma (PTC) is considered an inflammation-driven cancer. However, a systematic investigation of the relationship between the tumour immune microenvironment and prognosis in PTC has not been conducted. Methods: A prognostic model based on differentially expressed genes (DEGs) and progression-free survival (PFS) data from the Cancer Genome Atlas (TCGA) was established by least absolute shrinkage and selection operator (LASSO) and multivariate Cox analyses. 502 PTC cases were divided into low prognostic riskscore (PR) (L-PR) and high PR (H-PR) groups according to the median PR. We compared the immune characteristics between groups and verified these differences in validation cohorts. Furthermore, we explored cancer stem cells (CSCs) and tumour mutation burden (TMB) to explain the prognostic results. Findings: A prognostic signature (PR) based on 13 DEGs performed well in prognostic prediction (5-year area under the curve (AUC)= 0.861). The PR was positively correlated with age, stage, T classification, metastasis, RAS mutation, and subtypes as follicular or tall cell PTC. Importantly, the H-PR group, which had poor prognostic features, exhibited four main characteristics: comprehensive weakening of the immune system (immune escape) that was not observed in the L-PR group, a higher ratio of tumour-promoting immune cells, more CSCs, and a higher TMB than the L-PR group. Interpretation: Our prognostic model can effectively predict the prognosis and immune characteristics of PTC and revealed that immune escape, tumour-promoting immune infiltration patterns and tumour heterogeneity in the tumour microenvironment (TME) could be mechanisms of poor prognosis in PTC. Funding Statement: National Natural Science Foundation of China (81600602). Declaration of Interests: The authors stated: None. Ethics Approval Statement: Not required.

MiRNA-21 promotes cell proliferation and invasion via VHL/PI3K/AKT in papillary thyroid carcinoma.

Papillary thyroid carcinoma (PTC) is the main kind of thyroid carcinoma, most of which are diagnosed in women. MiR-21 has been reported to be upregulated in multiple cancers to effect tumor growth. However, the role of miR-21 in PTC development remains unclear. In this present study, miR-21 and VHL expressions in PTC tissues and cells were evaluated by RT-qPCR and/or western blot. MTT assay and transwell assay were employed to assess cell proliferative and invasive abilities, respectively. Luciferase reporter assay was carried out to identify the target of miR-21and explore its roles in PTC. MiR-21 was upregulated in PTC tissues and cells. Ectopic of miR-21 expression promoted cell proliferative and invasive abilities, while knockdown miR-21 suppressed these in TPC-1 and BCPAP cells. Overexpression of miR-21 predicted poor prognosis in PTC. What is more, luciferase reporter assays showed miR-21 can directly target VHL in PTC cells. Knockdown of miR-21 expression inhibited TPC-1 and BCPAP cell invasion-mediated EMT and proliferation through the PI3K/AKT pathway. In addition, VHL reverses partial function of miR-21 on PTC cell proliferation and invasion. MiR-21 can inhibit cell proliferation and invasion by regulated VHL in PTC cells. The newly identified miR-21/VHL axis might provide a novel insight into the pathogenesis and therapy of PTC.

Expression of Notch-1 and recurrence-related factors in papillary thyroid carcinoma

Objective To analyze the expression of Notch-1 and correlation between Notch-1 expression and recurrence-related factors in papillary thyroid carcinoma (PTC). Methods Immunohistochemical staining was performed on 235 paraffin tissues to detect the expression of Notch-1. Combining the clinicopathological and prognostic data, the correlation between Notch-1 expression and recurrence was analyzed. Results Notch-1 had higher expression in the relapsed PTC patients than in the patients without recurrence (χ2=20.164, P 0.05). Multiple analysis showed that Notch-1 expression and ETE were the independent factors in relapsed PTC. Conclusion High expression of Notch-1 indicates poor prognosis of PTC and Notch-1 could be an effective indicator for the recurrent PTC. Key words: Thyroid neoplasms; Prognosis; Notch-1; Recurrence

BRAF mutation in papillary thyroid carcinoma: Predictive value for long-term prognosis and radioiodine sensitivity

BRAF pV600E mutation is the most common oncogenic event and the most specific mutation for papillary thyroid carcinoma (PTC). Many studies over the last decade have shown a direct relationship between BRAF mutation and aggressive tumour characteristics, resulting in poor prognosis. However, several recent studies have suggested that BRAF mutation is not associated with poor prognosis of PTC. The present study was designed to evaluate the association between BRAF mutation with clinicopathological factors and tumour recurrence. In this retrospective study, BRAF mutation status was examined by direct sequencing on paraffin-embedded tumour specimens from 46 patients undergoing surgery for PTC in our institution from 1985 to 2000. The relationship between BRAF mutation and gender, advanced age, extrathyroid extension, multifocal tumour, cervical lymph node metastasis, tumour size and advanced pT stage of PTC and its predictive role for the risk of tumour recurrence were investigated with a median follow-up of 10.1 (±6.5)years. BRAF mutation was detected in 20 of the 46 patients (43.5%) included in the study. No statistically significant correlation was demonstrated between the presence of BRAF mutation and the various clinicopathological factors studied. No significant difference in tumour recurrence rate or radioiodine sensitivity was observed between the two subgroups: mutant BRAF and wild-type BRAF. Although BRAF mutation appears to play a role in local tumour progression, it is not a risk factor for poor prognosis or tumour recurrence in PTC.

Preoperative subclinical hypothyroidism in patients with papillary thyroid carcinoma

ObjectiveTo assess the effect of preoperative subclinical hypothyroidism on prognosis and on the tumour's clinicopathological features at initial diagnosis of papillary thyroid carcinoma (PTC). Materials and methods328 patients who underwent surgery for PTC between January 2001 and December 2006 were enrolled in this study. Of these, we compared 35 patients with preoperative subclinical hypothyroidism with 257 patients who were euthyroid before the operation, with respect to clinicopathological characteristics and prognosis. ResultsNo significant differences were observed in tumour size, extrathyroidal extension, and multifocality between subclinical hypothyroidism and euthyroid patients. Patients with subclinical hypothyroidism had a considerably lower percentage of lymph node metastasis than did euthyroid patients (8.6% vs. 21.8%, p=0.068). Although preoperative subclinical hypothyroidism decreased the risk of lymph node metastasis at 0.313 of odds ratio in the multivariate analysis, its significance was not verified (95% confidence internal, 0.089–1.092; p=0.068). Patients with preoperative subclinical hypothyroidism tended to have a better prognosis than did preoperative euthyroid patients, for both recurrence (2.9% vs. 14.0%, p=0.099) and 7-year disease-free survival (97.1% vs. 87.8%, p=0.079), during the 82-month mean follow-up period. However, even as thyroid-stimulating hormone (TSH) concentration increased, there were no consistent relationships observed between the TSH levels and the prognostic parameters. ConclusionWe could find neither a consistent positive nor a negative linear relationship between TSH levels and several prognostic parameters, indicating that subclinical hypothyroidism with elevated TSH is not an independent predictor of tumour aggressiveness and poor prognosis in PTC.

Prognostic Implications of miR-146b Expression and Its Functional Role in Papillary Thyroid Carcinoma

Recent studies suggest that miR-146b deregulation in papillary thyroid carcinoma (PTC) was associated with advanced tumor characteristics. However, the influence of miR-146b expression on the prognosis of PTC remains unknown. We sought to correlate tumor expression levels of miR-146b with the prognosis of a previously reported PTC cohort and reveal the underlying mechanisms via a PTC cell line model. Expression levels of miR-146b were assessed via quantitative real-time PCR in 71 cases of PTC with distinct clinico-pathogenetic characteristics. All patients were classified into the disease-free or active disease group, based on their medical records at the end of the follow-up period. In vitro gain-of-function experiments were performed in a BCPAP human papillary thyroid cancer cell line model, which harbored the homozygous mutation of BRAF. BCPAP cells were transfected with a mimic-miR-146b and nonspecific microRNA (miRNA) control to determine whether miR-146b overexpression promotes cell migration and invasion. Proliferation assay, colony formation assay, and chemotherapy-induced apoptosis were also determined. Multivariate logistic regression analysis demonstrated advanced tumor stage, presence of cervical lymph node metastasis, and miR-146b expression were independent risk factors for poor prognosis in PTC. Patients with higher miR-146b expression levels had significantly poorer overall survival compared with those with lower miR-146b levels. The associated hazard ratio was 3.92 (95% confidence interval, 1.73-8.86, log-rank P < .05). Overexpression of miR-146b significantly increased cell migration and invasiveness. Furthermore, miR-146b also increased resistance to chemotherapy-induced apoptosis. Our results suggest that miR-146b is a novel prognostic factor of PTC. Furthermore, in vitro functional studies provided the mechanistic explanation for miR-146b in tumor aggressiveness. These results enhance understanding of the molecular mechanisms involved in tumor aggressiveness in PTC, provide new prognostic biomarkers, and ultimately offer new leads for developing therapies for PTC.

Clinical and Pathological Features and the BRAFV600E Mutation in Patients with Papillary Thyroid Carcinoma with and without Concurrent Hashimoto Thyroiditis

It has been reported that patients with papillary thyroid carcinoma (PTC) have a high incidence of background Hashimoto thyroiditis (HT); however, the linkage of HT to PTC is controversial. Recent studies have shown that the prevalence of activating point mutations in BRAFV600E is much higher (73-86%) in Korea than in Western countries (29-69%), and associated with a poor prognosis in PTC. The purpose of the present study was to investigate the frequency of the BRAFV600E mutation in PTC with and without HT, and to determine clinical and pathological features that were associated with concomitant HT and PTC. Fine-needle aspiration slides from 101 patients with surgically confirmed PTC were studied. The DNA was extracted from the atypical cells that were scraped from slides. It was then analyzed for the BRAFV600E mutation by pyrosequencing. In addition, the presence of background HT in surgical specimens and other clinical and pathological features of the patients were characterized. HT was present in 37 (36.6%) of the patients. The BRAFV600E mutation was present in 27 (72.9%) of patients with HT but was present in 61 (95.3%) of patients without HT ( p#0.01). The inverse correlation of concurrent HT with the BRAFV600E mutation was significant for both males and females ( p < 0.01). The presence of background HT was not associated with tumor size, extrathyroidal invasion, lymph node (LN) metastasis, or tumor stage. The patients were younger in the group without background HT (44.1 +/- 13.2 vs. 49.8 +/- 13.9, p 1/40.05). The BRAFV600E mutation was present in 88 (87.1%) of the 101 patients with PTC. The presence of the BRAFV600E mutation was significantly associated with LN metastasis ( p < 0.02; odds ratio, 6.24; 95% confidence interval, 1.51-25.79). In Korean patients with PTC, the BRAFV600E mutation is associated with a lower frequency of background HT and a high frequency of LN metastasis.