Comprehensive Analysis of Prognostic Alternative Splicing Signature Reveals Recurrence Predictor for Papillary Thyroid Cancer

BackgroundAlternative splicing (AS) plays a key role in the diversity of proteins and is closely associated with tumorigenicity. The aim of this study was to systemically analyze RNA alternative splicing (AS) and identify its prognostic value for papillary thyroid cancer (PTC).MethodsAS percent-splice-in (PSI) data of 430 patients with PTC were downloaded from the TCGA SpliceSeq database. We successfully identified recurrence-free survival (RFS)-associated AS events through univariate Cox regression, LASSO regression and multivariate regression and then constructed different types of prognostic prediction models. Gene function enrichment analysis revealed the relevant signaling pathways involved in RFS-related AS events. Simultaneously, a regulatory network diagram of AS and splicing factors (SFs) was established.ResultsWe identified 1397 RFS-related AS events which could be used as the potential prognostic biomarkers for PTC. Based on these RFS-related AS events, we constructed a ten-AS event prognostic prediction signature that could distinguish high-and low-risk patients and was highly capable of predicting PTC patient prognosis. ROC curve analysis revealed the excellent predictive ability of the ten-AS events model, with an area under the curve (AUC) value of 0.889; the highest prediction intensity for one-year RFS was 0.923, indicating that the model could be used as a prognostic biomarker for PTC. In addition, the nomogram constructed by the risk score of the ten-AS model also showed high predictive efficiency for the prognosis of PTC patients. Finally, the constructed SF-AS network diagram revealed the regulatory role of SFs in PTC.ConclusionThrough the limited analysis, AS events could be regarded as reliable prognostic biomarkers for PTC. The splicing correlation network also provided new insight into the potential molecular mechanisms of PTC.

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A 5′-tRNA halve, tiRNA-Gly promotes cell proliferation and migration via binding to RBM17 and inducing alternative splicing in papillary thyroid cancer

Journal of Experimental & Clinical Cancer Research ◽

10.1186/s13046-021-02024-3 ◽

2021 ◽

Vol 40 (1) ◽

Author(s):

Litao Han ◽

Hejing Lai ◽

Yichen Yang ◽

Jiaqian Hu ◽

Zhe Li ◽

...

Keyword(s):

Cell Proliferation ◽

Thyroid Cancer ◽

Alternative Splicing ◽

Papillary Thyroid Cancer ◽

Rna Binding ◽

Rna Binding Protein ◽

Papillary Thyroid ◽

Cell Proliferation And Migration ◽

And Migration ◽

Proliferation And Migration

Abstract Background tRNA-derived small noncoding RNAs (sncRNAs) are mainly categorized into tRNA halves (tiRNAs) and fragments (tRFs). Biological functions of tiRNAs in human solid tumor are attracting more and more attention, but researches concerning the mechanisms in tiRNAs-mediated tumorigenesis are rarely. The direct regulatory relationship between tiRNAs and splicing-related proteins remain elusive. Methods Papillary thyroid carcinoma (PTC) associated tRNA fragments were screened by tRNA fragments deep sequencing and validated by qRT-PCR and Northern Blot in PTC tissues. The biological function of tRNA fragments were assessed by cell counting kit, transwells and subcutaneous transplantation tumor of nude mice. For mechanistic study, tRNA fragments pull-down, RNA immunoprecipitation, Western Blot, Immunofluorescence, Immunohistochemical staining were performed. Results Herein, we have identified a 33 nt tiRNA-Gly significantly increases in papillary thyroid cancer (PTC) based on tRFs & tiRNAs sequencing. The ectopic expression of tiRNA-Gly promotes cell proliferation and migration, whereas down-regulation of tiRNA-Gly exhibits reverse effects. Mechanistic investigations reveal tiRNA-Gly directly bind the UHM domain of a splicing-related RNA-binding protein RBM17. The interaction with tiRNA-Gly could translocate RBM17 from cytoplasm into nucleus. In addition, tiRNA-Gly increases RBM17 protein expression via inhibiting its degradation in a ubiquitin/proteasome-dependent way. Moreover, RBM17 level in tiRNA-Gly high-expressing human PTC tissues is upregulated. In vivo mouse model shows that suppression of tiRNA-Gly decreases RBM17 expression. Importantly, tiRNA-Gly can induce exon 16 splicing of MAP4K4 mRNA leading to phosphorylation of downstream signaling pathway, which is RBM17 dependent. Conclusions Our study firstly illustrates tiRNA-Gly can directly bind to RBM17 and display oncogenic effect via RBM17-mediated alternative splicing. This fully novel model broadens our understanding of molecular mechanism in which tRNA fragment in tumor cells directly bind RNA binding protein and play a role in alternative splicing.

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TREM1 fosters an immunosuppressive tumor microenvironment in papillary thyroid cancer

Endocrine Related Cancer ◽

10.1530/erc-21-0297 ◽

2021 ◽

Author(s):

Yang Zhao ◽

Cangang Zhang ◽

Yanan Zhu ◽

Xi Ding ◽

Yikun Zhou ◽

...

Keyword(s):

T Cells ◽

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Molecular Mechanisms ◽

Methylation Status ◽

Disease Free Survival ◽

Papillary Thyroid ◽

Advanced Tumor ◽

Tumor Stages ◽

Immunosuppressive Microenvironment

The immunosuppressive microenvironment is associated with poor prognosis in papillary thyroid cancer (PTC); however, the molecular mechanisms involved are unknown. Among triggering receptor expressed on myeloid cell (TREM) family, we found that TREM1 expression in PTC was significantly higher than that in normal tissues. TREM1 overexpression was associated with BRAFV600E profiles and advanced tumor stages. Furthermore, TREM1 mRNA expression was negatively correlated with promoter methylation status. Specifically, hypomethylation of CpG site cg06196379 in the TREM1 promoter was related with poor patient disease free survival (DFS) and a high PTC recurrence rate. Mechanistically, TREM1 was mainly expressed in malignant epithelial cells but not macrophages in PTC by single-cell analysis. PTC tissues with high TREM1 levels had enhanced infiltration of regulatory T cells (Tregs) and decreased infiltration of CD8+ T cells. Our study confirms that hypomethylation-mediated overexpression of TREM1 in PTC cells promotes an immunosuppressive microenvironment by enhancing Treg infiltration. We recommend the future use of therapeutic strategy targeting TREM1 for the treatment of PTC.

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Annual Hazard Rate of Recurrence in Middle Eastern Papillary Thyroid Cancer over a Long-Term Follow-Up

Cancers ◽

10.3390/cancers12123624 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3624

Author(s):

Abdul K. Siraj ◽

Sandeep Kumar Parvathareddy ◽

Zeeshan Qadri ◽

Khawar Siddiqui ◽

Saif S. Al-Sobhi ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Hazard Rate ◽

Tumor Recurrence ◽

Cox Regression ◽

Middle Eastern ◽

Treatment Strategies ◽

Recurrence Risk ◽

Papillary Thyroid ◽

Cox Regression Analysis

Predicting the pattern of recurrence in papillary thyroid cancer (PTC) is necessary to establish optimal surveillance and treatment strategies. We analyzed changes in hazard rate (HR) for tumor recurrence over time in 1201 unselected Middle Eastern PTC patients. The changes in risk were further analyzed according to clinical variables predictive of early (≤5 years) and late (>5 years) recurrence using Cox regression analysis to identify patient populations that remain at risk. Tumor recurrence was noted in 18.4% (221/1201) patients. The annualized hazard of PTC recurrence was highest during the first 5 years (2.8%), peaking between 1 and 2 years (3.7%), with a second smaller peak between 13 and 14 years (3.2%). Patients receiving radioactive iodine (RAI) therapy had lower recurrence hazard compared to those who did not (1.5% vs. 2.7%, p = 0.0001). Importantly, this difference was significant even in intermediate-risk PTC patients (0.7% vs. 2.3%; p = 0.0001). Interestingly, patients aged ≥55 years and having lymph node metastasis were at persistent risk for late recurrence. In conclusion, we confirmed the validity of the double-peaked time-varying pattern for recurrence risk in Middle Eastern PTC patients and our findings could help in formulating individualized treatment and surveillance plans.

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Nomogram-Based New Recurrence Predicting System in Early-Stage Papillary Thyroid Cancer

International Journal of Endocrinology ◽

10.1155/2019/1029092 ◽

2019 ◽

Vol 2019 ◽

pp. 1-7

Author(s):

Yongfeng Ding ◽

Zhuochao Mao ◽

Jiaying Ruan ◽

Xingyun Su ◽

Linrong Li ◽

...

Keyword(s):

Risk Factors ◽

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Cox Regression ◽

Early Stage ◽

Cox Model ◽

Staging System ◽

Papillary Thyroid ◽

Cox Regression Analysis ◽

Ajcc Staging

Background and Objectives. The clinicopathological risk factors to predict recurrence of papillary thyroid cancer (PTC) patients remain controversial. Methods. PTC patients treated with thyroidectomy between January 1997 and December 2011 at the First Affiliated Hospital of Zhejiang University (Zhejiang cohort) were included. Multivariate Cox regression analysis was conducted to identify independent recurrence predictors. Then, the nomogram model for predicting probability of recurrence was built. Results. According to Zhejiang cohort (N = 1,697), we found that the 10-year event-free survival (EFS) rates of PTC patients with early-stage (TNM stages I, II, and III) were not well discriminated (91.6%, 89.0%, and 90.7%; P=0.768). The multivariate Cox model identified age, bilaterality, tumor size, and nodal status as independent risk factors for tumor recurrence in PTC patients with TNM stages I–III. We then developed a nomogram with the C-index 0.70 (95% CI, 0.64 to 0.76), which was significantly higher (P<0.0001) than the AJCC staging system (0.52). In the validation group, the C-index remained at a similar level. Conclusions. In this study, we build up a new recurrence predicting system and establish a nomogram for early-stage PTC patients. This prognostic model may better predict individualized outcomes and conduct personalized treatments.

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Downregulation of miR-519d-3p is Associated with Poor Outcomes and Facilitates Tumor Progression in Papillary Thyroid Cancer by Regulating FOXQ1

Hormone and Metabolic Research ◽

10.1055/a-1560-2827 ◽

2021 ◽

Vol 53 (09) ◽

pp. 625-632

Author(s):

Pihong Li ◽

Xiaoyu Pan ◽

Zhouci Zheng ◽

Yihan Sun ◽

Yifan Han ◽

...

Keyword(s):

Thyroid Cancer ◽

Tumor Progression ◽

Papillary Thyroid Cancer ◽

Cox Regression ◽

Biological Effects ◽

Pearson Correlation ◽

Progression Free Survival ◽

Luciferase Reporter ◽

Migration And Invasion ◽

Papillary Thyroid

AbstractMicroRNA-519d-3p (miR-519d-3p) has emerged as a tumor suppressor in several human cancers. But whether miR-519d-3p is involved in papillary thyroid cancer (PTC) remains elusive. In this study, we investigated the potential relevance of miR-miR-519d-3p in PTC. A retrospective study of 119 PTCs was carried out. The RT-qPCR analysis was used to measure the expression of miR-519d-3p and FOXQ1 in PTC tissues and cells. Chi-square test, Kaplan–Meier curve analysis, and multivariate Cox regression analyses were performed to assess the clinical and prognostic value of miR-519d-3p in PTC. Then cellular experiments were used to explore its biological effects on PTC cells. Finally, the Pearson correlation coefficient, dual-luciferase reporter assay, and rescue experiments were used to analyze the association between miR-519d-3p and FOXQ1. miR-519d-3p was significantly downregulated in PTC tissues and cell lines. The decreased expression of miR-519d-3p was associated with reduced overall survival and progression-free survival of patients. The proliferative, migratory, and invasive abilities of cells were blocked or elevated after upregulation or downregulation of miR-519d-3p, while FOXQ1 reversed these cellular behaviors caused after upregulation or knockdown of miR-519d-3p. In conclusion, miR-519d-3p was downregulated in PTC and associated with OS and PFS of patients. MiR-519d-3p may be a tumor-inhibiting miRNA in PTC, and that miR-519d-3p/FOXQ1 axis mediated PTC tumor progression from cell proliferation, migration, and invasion in PTC cells.

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KIFC1 accelerates the proliferation, migration and invasion of papillary thyroid cancer cells via MAPK signaling

10.21203/rs.3.rs-39548/v1 ◽

2020 ◽

Author(s):

Chunlei Nie ◽

Jihua Han ◽

Wen Bi ◽

Lili Chen ◽

Jiawei Yu ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Molecular Mechanisms ◽

Epithelial Mesenchymal Transition ◽

Mapk Signaling ◽

Migration And Invasion ◽

Papillary Thyroid ◽

Differentiation Markers ◽

Mesenchymal Transition ◽

Extrathyroidal Invasion

Abstract Kinesin family member C1 (KIFC1) acts as a kind of minus end-directed motorized protein and is considered as an oncogene of some cancer types. However, no studies have fully elucidated its biological activity and molecular mechanisms in papillary thyroid cancer (PTC). The study focused on reporting the overexpression of KIFC1 in cell lines and tissues of PTC. Moreover, clinicopathological features analysis showed that KIFC overexpression is significantly correlated with extrathyroidal invasion and lymph node metastasis. Knockdown of KIFC1 significantly reduced cell growth, migration and invasion in PTC cells, and concomitant increased levels of differentiation markers, such as Tg and Nis. Knockdown of KIFC1 markedly increased the expression level of epithelial cell marker (E-cadherin), and decreased the expression levels of epithelial-mesenchymal transition (EMT) related transcriptional factor N-cadherin, Snail and ZEB1. Further study revealed that knockdown of KIFC1 downregulated stemness markers ALDH2 and SOX2, and inhibited the MAPK signaling cascades and downstream signaling, including p-ERK, ERK, p-JNK, JNK, MMP2, and MMP9, which can affect the expression of the EMT associated factors. Taken together, we reported that KIFC1 might promoted the proliferation, migration and invasion of PTC cells and offer a candidate molecular target for therapeutic intervention.

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Blood-Rich Enhancement in Ultrasonography Predicts Worse Prognosis in Patients With Papillary Thyroid Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.546378 ◽

2021 ◽

Vol 10 ◽

Author(s):

Luying Gao ◽

Xuehua Xi ◽

Qiong Gao ◽

Jiajia Tang ◽

Xiao Yang ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Cox Regression ◽

Area Under The Curve ◽

Papillary Thyroid ◽

Predictive Values ◽

Incomplete Response ◽

Potential Association ◽

Contrast Enhanced ◽

Patient Prognosis

Contrast-enhanced ultrasound (CEUS) can be used to evaluate microcirculation in cancers, which in turn is associated with the biologic features and ultimately patient prognosis. We conducted a retrospective analysis to examine potential association between CEUS parameters and prognosis in patients with papillary thyroid cancer (PTC). The analysis included 306 patients who underwent CEUS prior to thyroidectomy at our center during a period from 2012 to 2019. Subjects with excellent response (ER) were compared to the non-ER group (including indeterminate response, biochemical incomplete response and structural incomplete response). During the median follow-up of 34 months, ER was observed in 195 (63.7%) subjects. The remaining 111 (36.3%) patients developed non-ER events, with distant metastasis in five (1.6%) cases. In a multivariate COX regression, non-ER event was associated with the male sex (OR = 1.83, 95%CI: 1.21–2.76) and blood-rich enhancement in CEUS (OR = 1.69, 95%CI: 1.04–2.75). Based on this finding, we developed a predictive model: high risk for developing non-ER events was defined as having both risk factors; low risk was defined as having none or only one risk. In receiver operating characteristic (ROC) analysis, the area under the curve was 0.59 (95%CI: 0.52–0.66). The sensitivity and specificity were 17.1 and 95.4%, respectively. The positive and negative predictive values were 67.9 and 66.9%, respectively. In conclusion, blood-rich enhancement in CEUS is associated with non-ER events after thyroidectomy in patients with PTC.

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MiR-9 and miR-21 as prognostic biomarkers for recurrence in papillary thyroid cancer

Clinical & Experimental Metastasis ◽

10.1007/s10585-015-9724-3 ◽

2015 ◽

Vol 32 (6) ◽

pp. 521-530 ◽

Cited By ~ 37

Author(s):

Adriana Sondermann ◽

Flavia Maziero Andreghetto ◽

Ana Carolina Bernardini Moulatlet ◽

Elivane da Silva Victor ◽

Marilia Germanos de Castro ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Prognostic Biomarkers ◽

Papillary Thyroid

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Overexpression of miR-127 Predicts Poor Prognosis and Contributes to the Progression of Papillary Thyroid Cancer by Targeting REPIN1

Hormone and Metabolic Research ◽

10.1055/a-1322-3160 ◽

2020 ◽

Author(s):

Yinghe Sun ◽

Wenhai Sun ◽

Hui Hua ◽

Jianhua Zhang ◽

Qianqian Yu ◽

...

Keyword(s):

Cell Proliferation ◽

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Poor Prognosis ◽

Cox Regression ◽

Tnm Stage ◽

Prognostic Indicators ◽

Migration And Invasion ◽

Papillary Thyroid ◽

Cox Regression Analysis

AbstractPapillary thyroid cancer (PTC) is a major kind of thyroid cancer with increasing recurrence and metastasis. MiR-127 has been demonstrated to play roles in many cancers with dysregulation. However, the function of miR-127 is still unknown. This study aimed to explore a novel biomarker for the progression and prognosis of PTC. A set of 118 patients with PTC were collected from the Affiliated Hospital of Qingdao University. qRT-PCR was used to detect the expression of miR-127 in PTC tissues and cells. The association between miR-127 expression and the clinicopathological features of patients were evaluated by the χ2 test, and the prognostic value of miR-127 was evaluated by Kaplan–Meier analysis and Cox regression analysis. The effect of miR-127 on cell proliferation, migration, and invasion of PTC was analyzed by CCK-8 and transwell assay. miR-127 was found to be upregulated in PTC tissues and cells correlated with the TNM stage and poor prognosis of PTC patients. MiR-127 and the TNM stage were considered as two independent prognostic indicators for PTC. Moreover, overexpression of miR-127 significantly enhanced cell proliferation, migration, and invasion of PTC by targeting REPIN1. miR-127 may be involved in the progression of PTC, which provides a new therapeutic strategy for PTC.

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Evaluation of Clinicopathological and Molecular Parameters on Disease Recurrence of Papillary Thyroid Cancer Patient: A Retrospective Observational Study

Cancers ◽

10.3390/cancers12123637 ◽

2020 ◽

Vol 12 (12) ◽

pp. 3637

Author(s):

Salvatore Sorrenti ◽

Giovanni Carbotta ◽

Filippo Maria Di Matteo ◽

Antonio Catania ◽

Daniele Pironi ◽

...

Keyword(s):

Thyroid Cancer ◽

Papillary Thyroid Cancer ◽

Cox Regression ◽

Cox Model ◽

Clinicopathological Parameters ◽

Papillary Thyroid ◽

Thyroid Cancer Patient ◽

Molecular Parameters ◽

Tall Cell ◽

The Impact

The American Joint Committee on Cancer has revised the Tumor-Node-Metastasis (TNM) staging system for papillary thyroid cancer (PTC) patients. We examined the impact of this new classification (TNM-8) on patient stratification and estimated the prognostic value of clinicopathological features for the disease-free interval (DFI) in a cohort of 1148 PTC patients. Kaplan–Meier analyses showed that all clinicopathological parameters analyzed, except age and multifocality, were associated significantly with DFI. Cox regression identified tall cell PTC variant and stage as independent risk factors for DFI. When the stage was replaced with age, tumor size, and lymph node (LN) metastases in the set of covariates, the lateral LN metastases stood out as the strongest independent predictor of DFI, followed by tall cell variant and age. A noteworthy result emerging from these analyzes is that regression models had lower Akaike and Bayesian information criterions if variables were categorized based on the TNM-7. In addition, we examined data from a different PTC patient cohort, acquired from The Cancer Genome Atlas database, to verify whether the DFI prediction could be enhanced by further clinicopathological and molecular parameters. However, none of these was found to be a significant predictor of DFI in the Cox model.

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