Duo Wen

Long intergenic non-coding RNA 271 is predictive of a poorer prognosis of papillary thyroid cancer

A number of long non-coding RNAs (lncRNAs) have been found to play critical roles in oncogenesis and tumor progression. We aimed to investigate whether lncRNAs could act as prognostic biomarkers for papillary thyroid cancer (PTC) that may assist us in evaluating disease status and prognosis for patients. We found 220 lncRNAs with expression alteration from the annotated 2773 lncRNAs approved by the HUGO gene nomenclature committee in The Cancer Genome Atlas (TCGA) dataset, of which FAM41C, CTBP1-AS2, LINC00271, HAR1A, LINC00310 and HAS2-AS1 were associated with recurrence. After adjusting classical clinicopathogical factors and BRAFV600E mutation, LINC00271 was found to be an independent risk factor for extrathyroidal extension, lymph node metastasis, advanced tumor stage III/IV and recurrence in multivariate analyses. Additionally, LINC00271 expression was significantly downregulated in PTCs versus adjacent normal tissues (P < 0.001). The Gene Set Enrichment Analysis (GSEA) revealed that genes associated with cell adhesion molecules, cell cycle, P53 signaling pathway and JAK/STAT signaling pathway were remarkably enriched in lower-LINC00271 versus higher-LINC00271 tumors. In conclusion, LINC00271 was identified as a possible suppressor gene in PTC in our study, and it may serve as a potential predictor of poor prognoses in PTC.

Yes-associated protein 1 promotes papillary thyroid cancer cell proliferation by activating the ERK/MAPK signaling pathway

Yes-associated protein 1 (YAP1) stimulates cell proliferation, epithelial-to-mesenchymal transition, invasion and metastasis in several cancers. Here, we investigated the involvement of YAP1 in papillary thyroid carcinoma (PTC) by assessing YAP1 mRNA and protein levels in PTC tissues and matched normal thyroid epithelial tissues from 50 patients. YAP1 mRNA and protein levels were higher in PTC tumor tissues than in control tissues, and correlated positively with the levels of proliferation-related genes (KI67 and c-MYC). We also used lentiviral vectors to overexpress or silence YAP1 expression in the K1 PTC cell line so that we could investigate the effects of YAP1 on cancer cell proliferation. YAP1 overexpression enhanced PTC cell proliferation by activating ERK1/2 and AKT, and these effects were impaired by treating the cells with the MEK inhibitor U0126 or the AKT inhibitor GSK690693. Finally, YAP1 overexpression dramatically induced growth of tumors from PTC cells in a xenograft mouse model. These results suggest that YAP1 enhances cell proliferation in PTC, and thus may be a promising target in the treatment of PTC.

Metastatic lymph node ratio can further stratify risk for mortality in medullary thyroid cancer patients: A population-based analysis

Medullary thyroid cancer (MTC) has a propensity to cervical lymph node metastases (LNM). Recent studies have shown that both the number of involved lymph nodes (LNs) and the metastatic lymph node ratio (MLNR) confer prognostic information. This study was to determine the predictive value of MLNR on cancer-specific survival (CSS) in SEER (Surveillance, Epidemiology and End Results)-registered MTC patients treated with thyroidectomy and lymphadenectomy between 1991 and 2012, investigate the cutoff points for MLNR in stratifying risk of mortality and provide evidence for selection of appropriate treatment strategies. X-tile program determined 0.5 as optimal cut-off value for MLNR in terms of CSS in 890 MTC patients. According to multivariate Cox regression analysis, MLNR (0.50–1.00) is a significant independent prognostic factor for CSS (hazard ratio 2.161, 95% confidence interval 1.327–3.519, p=0.002). MLNR (0.50–1.00) has a greater prognostic impact on CSS in female, non-Hispanic white, T3/4, N1b and M1 patients. The lymph node yield (LNY) influences the effect of MLNR on CSS; LNY ≥9 results in MLNR (0.50–1.00) having a higher HR for CSS than MLNR (0.00-0.49). In conclusion, higher MLNRs predict poorer survival in MTC patients. Eradication of involved nodes ensures accurate staging and maximizes the ability of MLNR to predict prognosis.

Tumor size interpretation for predicting cervical lymph node metastasis using a differentiated thyroid cancer risk model

Lymph node metastasis (LNM) is common in differentiated thyroid cancer (DTC), but management of clinically negative DTC is controversial. This study evaluated primary tumor size as a predictor of LNM. Multivariate logistic regression analysis was used for DTC patients who were treated with surgery between 2002 and 2012 in the Surveillance, Epidemiology, and End Results (SEER) database, to determine the association of tumor size at 10 mm increments with LNM. A predictive model was then developed to estimate the risk of LNM in DTC, using tumor size and other clinicopathological characteristics identified from the multivariate analysis. We identified 80,565 eligible patients with DTC in the SEER database. Final histology confirmed 9,896 (12.3%) cases affected with N1a disease and 8,194 (10.2%) cases with N1b disease. After the patients were classified into subgroups by tumor size, we found that the percentages of male sex, white race, follicular histology, gross extrathyroidal extension, lateral lymph node metastasis, and distant metastasis gradually increased with size. In multivariate analysis, tumor size was a significant independent prognostic factor for LNM; in particular, the odds ratio for lateral lymph node metastasis continued to increase by size relative to a 1–10 mm baseline. The coefficient for tumor size in the LNM predictive model waŝ0.20, indicating extra change in log(odds ratio) for LNM as 0.2 per unit increment in size relative to baseline. In conclusion, larger tumors are likely to have aggressive features and metastasize to a cervical compartment. Multistratification by size could provide more precise estimates of the likelihood of LNM before surgery.

Verteporfin inhibits papillary thyroid cancer cells proliferation and cell cycle through ERK1/2 signaling pathway

Verteporfin, a FDA approved second-generation photosensitizer, has been demonstrated to have anticancer activity in various tumors, but not including papillary thyroid cancer (PTC). In current pre-clinical pilot study, we investigate the effect of verteporfin on proliferation, apoptosis, cell cycle and tumor growth of PTC. Our results indicate verteporfin attenuates cell proliferation, arrests cell cycle in G2/S phase and induces apoptosis of PTC cells. Moreover, treatment of verteporfin dramatically suppresses tumor growth from PTC cells in xenograft mouse model. We further illustrate that exposure to MEK inhibitor U0126 inactivates phosphorylation of ERK1/2 and MEK in verteporfin-treated PTC cells. These data suggest verteporfin exhibits inhibitory effect on PTC cells proliferation and cell cycle partially via ERK1/2 signalling pathway, which strongly encourages the further application of verteporfin in the treatment against PTC.

Clinicopathological and Survival Outcomes of Well-Differentiated Thyroid Carcinoma Undergoing Dedifferentiation: A Retrospective Study from FUSCC

Background Recently, several studies have reported that dedifferentiation occurs in fatal well-differentiated thyroid cancer (WDTC) cases. This study aimed at investigating the clinicopathological characteristics of WDTC undergoing dedifferentiation. Methods A total of 63 WDTC patients harboring dedifferentiated phenotype were enrolled in the study. The Kaplan-Meier method and Cox regression analysis were used to perform survival analyses. Harrell index of concordance (C-index) and Akaike information criterion (AIC) were calculated to compare the predictive value for prognosis among several prognostic classification systems. Results The median cause-specific survival (CSS) of patients was 138 months, with the CSS rate of 64.0% and 53.3% at 5 and 10 years, respectively. Presence of the anaplastic thyroid cancer (ATC) phenotype significantly increased the risk of poor CSS (P = 0.033), and age was the only independent risk factor for disease progression (P = 0.015). The C-index and AIC of the age, grade, extent, size (AGES) prognostic classification system for the CSS were 0.723 and 59.937, respectively. Conclusions The presence of dedifferentiated phenotypes can be responsible for the poor outcomes in WDTC patients. The AGES system demonstrates to be an optimal prognostic system for WDTC undergoing dedifferentiation.

Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/β-catenin signaling and sensitizes cancer cells to FH535 therapy

The incidence of thyroid cancer has increased worldwide at a rate higher than that of any other cancer. CSN6 is overexpressed in many types of cancers, and such expression is linked to oncogenic activity. However, the detailed biological functions of CSN6 in papillary thyroid cancer (PTC) have not been well characterized. We investigated CSN6 expression in PTC specimens and cell lines. We used short‐hairpin RNA‐mediated gene silencing to explore the biological effects of CSN6 depletion in PTC cells. The combined effects of CSN6 silencing and FH535 therapy were assessed in terms of cell viability. The mechanism by which CSN6 regulated β‐catenin expression was also analyzed. CSN6 levels were determined by real‐time polymerase chain reaction (PCR) (mRNA), Western blotting, and immunochemistry (protein). The CCK‐8 and migration assays and orthotopic xenograft transplantation were used to investigate the biological effects of CSN6. We assessed the combined effects of CSN6 silencing and FH535 on cell viability in vitro. We also analyzed the relationship between the CSN6 level and clinical pathological status. CSN6 was overexpressed in human PTCs, and loss of CSN6 attenuated tumor proliferation and migration both in vitro and in vivo. CSN6 stabilized β‐catenin and facilitated the epidermal‐to‐mesenchymal transition (EMT) in PTC cells. CSN6 positively regulated β‐catenin expression in a β‐Trcp‐dependent manner and triggered expression of several EMT‐related genes regulated by β‐catenin. CSN6 silencing sensitized PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway. Finally, in PTC patients, the level of CSN6 was significantly (inversely) correlated with tumor size, the presence of multifocal lesions, and TNM stage. CSN6 overexpression in PTC is a strong indicator of enhanced tumor aggressiveness. CSN6 promotes PTC progression by inducing the EMT. CSN6 knockdown sensitizes PTC cells to FH535 therapy via downregulation of the Wnt/β–catenin signaling pathway.

Corrigendum: Long intergenic non-coding RNA 271 is predictive of a poorer prognosis of papillary thyroid cancer

Scientific Reports 6: Article number: 36973; published online: 11 November 2016; updated: 09 February 2017 This Article contains errors in Table 1 and Table 4. The correct Table 1 and Table 4 appear below as Table 1 and Table 2 respectively.

Mediastinal Lymph Node Metastases in Thyroid Cancer: Characteristics, Predictive Factors, and Prognosis

Background Mediastinal lymph node metastases (MLNM) have not been extensively studied. The aim of this study is to investigate the characteristics, predictive factors, and prognosis of MLNM in thyroid cancer. Methods This is a retrospective study based on the thyroid cancer patients with MLNM at our institution from 2008 to 2015. Results In total, 73 thyroid cancer patients with positive MLNM were included in this study. It contained sixty patients (82.2%) with papillary thyroid carcinoma (PTC), twelve (16.4%) with medullary thyroid carcinoma, and one (1.4%) with anaplastic thyroid carcinoma. Forty-eight patients had the surgery as initial treatment. Fifty-three (72.6%) patients remained disease-free, and fifteen (20.5%) developed a regional recurrence. Distant metastases occurred in four (5.5%) patients and five (6.8%) patients died. Five-year overall survival rate and disease-free survival (DFS) rate of the PTC patients for initial treatment are 95.4% and 77.2%, respectively. Extrathyroidal extension and multiple lymph nodes involved were associated with DFS in PTC patients. Conclusions Initial therapeutic control is very important for the thyroid cancer patients. Extrathyroidal extension and multiple mediastinal lymph nodes involved were the influence factors of prognosis in the thyroid cancer patients with MLNM.