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Breast cancer has become the most commonly diagnosed cancer. Heterogeneous nuclear ribonucleoprotein C (HNRNPC), a reader of N6-methyladenosine (m6A), has been observed to be upregulated in various types of cancer. Nevertheless, the role of HNRNPC in breast cancer and whether it is regulated by m6A modification deserve further investigation. The expression of HNRNPC in breast cancer was examined by quantitative real-time polymerase chain reaction and western blot analysis. RNA immunoprecipitation was performed to validate the binding relationships between HNRNPC and WD repeat domain 77 (WDR77). The effects of HNRNPC and m6A regulators on WDR77 were investigated by actinomycin D assay. The experiments in vivo were conducted in xenograft models. In this research, we found that HNRNPC was highly expressed in breast cancer, and played a crucial role in cell growth, especially in the luminal subtype. HNRNPC could combine and stabilize WDR77 mRNA. WDR77 successively drove the G1/S phase transition in the cell cycle and promoted cell proliferation. Notably, this regulation axis was closely tied to the m6A modification status of WDR77 mRNA. Overall, a critical regulatory mechanism was identified, as well as promising targets for potential treatment strategies for luminal breast cancer.
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Neoplasias da Mama , Ribonucleoproteínas Nucleares Heterogêneas Grupo C , Feminino , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Ciclo Celular/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo C/metabolismo , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , RNA Mensageiro/genética , Fatores de Transcrição/genética , AdenosinaRESUMO
Background: Extrathyroidal extension is a major risk factor for poor prognosis in papillary thyroid cancer. However, the effect of different degrees of extrathyroidal extension on prognosis remains controversial. We performed a retrospective study to elucidate how the extent of extrathyroidal extension in papillary thyroid cancer affected the clinical prognosis of patients and its covariates. Methods: The study included 108,426 patients with papillary thyroid cancer. We categorized the extent of extension into none, capsule, strap muscles, and other organs. Three causal inference methods for retrospective studies, namely, inverse probability of treatment weighting, standardized mortality ratio weighting, and propensity score matching analysis, were used to minimize potential selection bias. Kaplan-Meier analysis and univariate Cox regression analyses were applied to analyze the precise effect of ETE on survival in papillary thyroid cancer patients. Results: In the Kaplan-Meier survival analysis, only extrathyroidal extension into or beyond the strap muscles was statistically significant for both overall survival (OS) and thyroid cancer-specific survival (TCSS). In univariate Cox regression analyses before and after matching or weighting based on causal inference, extrathyroidal extension into soft tissues or other organs is a high-risk factor for both overall survival and thyroid cancer-specific survival. Sensitivity analysis revealed that lower overall survival was observed in patients with older age (≥55) and larger tumor size (>2 cm) of papillary thyroid cancer with extrathyroidal extension into or beyond the strap muscles. Conclusions: Our study indicates that extrathyroidal extension into soft tissues or other organs is a high-risk factor in all papillary thyroid cancer. Even though invasion into the strap muscles did not seem to be a marker for poor prognosis, it still impaired the overall survival of patients with older age (≥55 years old) or larger tumor size (>2 cm). Further investigation is needed to confirm our results and to clarify further risk factors independent of extrathyroidal extension.
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Carcinoma Papilar , Neoplasias da Glândula Tireoide , Humanos , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/cirurgia , Câncer Papilífero da Tireoide/patologia , Estudos Retrospectivos , Pontuação de Propensão , Tireoidectomia , Carcinoma Papilar/patologia , Neoplasias da Glândula Tireoide/patologiaRESUMO
Background: Tumor microenvironment is essential for breast cancer progression and metastasis. Our study sets out to examine the genes affecting stromal and immune infiltration in breast cancer progression and prognosis. Materials and Methods: This work provides an approach for quantifying stromal and immune scores by using ESTIMATE algorithm based on gene expression matrix of breast cancer patients in TCGA database. We found differentially expressed genes (DEGs) through limma R package. Functional enrichments were accessed through Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. Besides, we constructed a protein-protein network, identified several hub genes in Cytoscape, and discovered functionally similar genes in GeneMANIA. Hub genes were validated with prognostic data by Kaplan-Meier analysis both in The Cancer Genome Atlas (TCGA) database and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) database and a meta-analysis of hub genes prognosis data was utilized in multiple databases. Furthermore, their relationship with infiltrating immune cells was evaluated by Tumor IMmune Estimation Resource (TIMER) web tool. Cox regression was utilized for overall survival (OS) and recurrence-free survival (RFS) in TCGA database and OS in METABRIC database in order to evaluate the impact of stromal and immune scores on patients prognosis. Results: One thousand and eighty-five breast cancer patients were investigated and 480 differentiated expressed genes (DEGs) were found based on the analysis of mRNA expression profiles. Functional analysis of DEGs revealed their potential functions in immune response and extracellular interaction. Protein-protein interaction network gave evidence of 10 hub genes. Some of the hub genes could be used as predictive markers for patients prognosis. In this study, we found that tumor purity and specific immune cells infiltration varied in response to hub genes expression. The multivariate cox regression highlighted the fact that immune score played a detrimental role in overall survival (HR = 0.45, 95% CI: 0.27-0.74, p = 0.002) and recurrence-free survival (HR = 0.41, 95% CI: 0.22-0.77, p = 0.006) in TCGA database. These result was confirmed in METABRIC database that immune score was a protector of OS (HR = 0.88, 95% CI: 0.77-0.99, p = 0.039). Conclusions: Our findings promote a better understanding of the potential genes behind the regulation of tumor microenvironment and cells infiltration. Immune score should be considered as a prognostic factor for patients' survival.
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BACKGROUND: Metabolic reprogramming, immune evasion and tumor-promoting inflammation are three hallmarks of cancer that provide new perspectives for understanding the biology of cancer. We aimed to figure out the relationship of tumor glycolysis and immune/inflammation function in the context of breast cancer, which is significant for deeper understanding of the biology, treatment and prognosis of breast cancer. METHODS: Using mRNA transcriptome data, tumor-infiltrating lymphocytes (TILs) maps based on digitized H&E-stained images and clinical information of breast cancer from The Cancer Genome Atlas projects (TCGA), we explored the expression and prognostic implications of glycolysis-related genes, as well as the enrichment scores and dual role of different immune/inflammation cells in the tumor microenvironment. The relationship between glycolysis activity and immune/inflammation function was studied by using the differential genes expression analysis, gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis, gene set enrichment analyses (GSEA) and correlation analysis. RESULTS: Most glycolysis-related genes had higher expression in breast cancer compared to normal tissue. Higher phosphoglycerate kinase 1 (PGK1) expression was associated with poor prognosis. High glycolysis group had upregulated immune/inflammation-related genes expression, upregulated immune/inflammation pathways especially IL-17 signaling pathway, higher enrichment of multiple immune/inflammation cells such as Th2 cells and macrophages. However, high glycolysis group was associated with lower infiltration of tumor-killing immune cells such as NKT cells and higher immune checkpoints expression such as PD-L1, CTLA4, FOXP3 and IDO1. CONCLUSIONS: In conclusion, the enhanced glycolysis activity of breast cancer was associated with pro-tumor immunity. The interaction between tumor glycolysis and immune/inflammation function may be mediated through IL-17 signaling pathway.
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Neoplasias , Glicólise , Humanos , Inflamação , Linfócitos do Interstício Tumoral , Prognóstico , Microambiente TumoralRESUMO
BACKGROUND: Columnar cell papillary thyroid carcinoma (CCPTC) is a rare variant of papillary thyroid carcinoma (PTC), whose prognosis, as defined by the American Thyroid Association (ATA) guidelines, is considered poor, although available evidence is insufficient for reliable assessment. This study aimed to investigate the CCPTC prognosis using the Surveillance, Epidemiology, and End Results (SEER) database. METHODS: Data of thyroid cancer patients, recorded from 2004 to 2013, were extracted to assess the CCPTC prognosis. All-cause and cancer-specific mortality rates associated with thyroid cancer types were evaluated using the Kaplan-Meier method and Cox proportional hazards regression. Propensity score matching analysis was used to adjust for potential confounders. RESULTS: Cancer-specific mortality per 1000 person-years was higher for CCPTC than for classic papillary thyroid cancer (CPTC) and follicular thyroid cancer (FTC). The multivariate Cox regression model revealed that the cancer-specific and all-cause mortality rates were higher for CCPTC than for CPTC but not FTC. However, propensity score matching analysis demonstrated a significantly lower survival for CCPTC than for both CPTC and FTC. CONCLUSIONS: Our findings provide evidence to support the poor prognosis associated with CCPTC. These findings may serve to improve the diagnosis of CCPTC, provide reliable reference data for clinical use, and increase the comprehensiveness of current guidelines.
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The prognosis of small cell thyroid carcinoma (SCTC) in a large cohort has not been well reported in the literature. In this study, we analyzed the mortality of SCTC, in comparison to medullary thyroid cancer (MTC) and anaplastic thyroid cancer (ATC), based on the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute, to determine the prognosis of SCTC. Information regarding patients with a diagnosis of MTC, ATC, or SCTC, between 2004 and 2013, was acquired from the SEER database. Patient survival curves were assessed by Cox proportional hazards regression analyses, Kaplan-Meier analyses, and log-rank tests. In a Kaplan-Meier analysis of the entire cohort of thyroid cancer patients, cancer-specific survival declined sharply for patients with SCTC, but it declined more modestly for patients with MTC. The cancer-specific survival was not significantly different between SCTC and ATC. Unadjusted Cox regression analysis showed that SCTC had a higher cancer-specific mortality than MTC but a similar prognosis as ATC. SCTC showed a higher cancer-specific mortality than MTC and ATC after adjustments for various confounding factors. SCTC was found to have a more highly lethal clinical course than MTC and had a similar death rate to ATC. Therefore, we recommend that aggressive, radical treatment like surgery or radiation should be performed for these patients.
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Carcinoma Neuroendócrino/patologia , Carcinoma de Células Pequenas/patologia , Carcinoma Anaplásico da Tireoide/patologia , Neoplasias da Glândula Tireoide/patologia , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
Thousands of lncRNAs have been identified but few have been functionally characterized in triple negative breast cancer (TNBC). LINC00152 was known as cytoskeleton regulator RNA (CYTOR) and expressed in various cancers including breast cancer. But the underlying molecular mechanism of LINC00152 in pathogenesis of TNBC have not been elucidated. In our study, we identified that LINC00152 expression was dramatically elevated in TNBC tissue and cells. Inhibition or overexpression of LINC00152 obviously increased or suppressed PTEN protein expression but did not affect the mRNA expression level. Our further experiments showed up-regulated LINC00152 in TNBC obviously enhanced NEDD4-1 mediated ubiquitination and degradation of PTEN protein. Finally, we demonstrated that YY1 bound with LINC00152 promotor and mostly inhibited the transcription of LINC00152. Furthermore, analysis of clinical samples resource retrieved from databases suggested high LINC00152 expression was correlated with ER or PR negative expression, late TNM stage and lymphatic invasion, as well as shorter overall survival time in patients. Consequently, this study firstly reveals that up-regulated LINC00152 mediates PTEN protein stability attenuation in TNBC.
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Regulação Neoplásica da Expressão Gênica , PTEN Fosfo-Hidrolase/genética , RNA Longo não Codificante/genética , Neoplasias de Mama Triplo Negativas/genética , Fator de Transcrição YY1/genética , Sítios de Ligação , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Progressão da Doença , Feminino , Genes Reporter , Humanos , Luciferases/genética , Luciferases/metabolismo , Metástase Linfática , Ubiquitina-Proteína Ligases Nedd4/genética , Ubiquitina-Proteína Ligases Nedd4/metabolismo , PTEN Fosfo-Hidrolase/metabolismo , Ligação Proteica , Estabilidade Proteica , Proteólise , RNA Longo não Codificante/antagonistas & inibidores , RNA Longo não Codificante/metabolismo , Transdução de Sinais , Análise de Sobrevida , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologia , Ubiquitinação , Fator de Transcrição YY1/metabolismoRESUMO
Systemic illustrations of spindle cell thyroid cancer (SCTC), based on a large cohort, are few. We investigated the prognosis of SCTC compared to the most common subtypes, papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC).Information of patients with a diagnosis of SCTC, PTC, or FTC, between 2004 and 2013, was obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Patient survival curves were investigated using Kaplan-Meier analyses, log-rank tests, and Cox proportional hazards regression analyses.In a Kaplan-Meier analysis of the entire cohort of thyroid cancer patients, cancer specific survival declined sharply for patients with SCTC, but declined more modestly for patients with PTC and FTC. Unadjusted Cox regression analysis and Kaplan-Meier curve analysis showed that SCTC had a poorer cancer-specific mortality and all-cause mortality compared to PTC and FTC. Similar results were obtained after adjustment for different confounding factors.Our study assessed the prognosis of SCTC, based on a large cohort, compared to PTC and FTC, and found relatively accurate hazard ratios of death rate in SCTC as compared to PTC and FTC. Thus, our findings would provide beneficial insights on patients with SCTC, and aid in treatment decision making, more radical treatment like total-thyoridectomy and/or plus central lymph node dissection should be performed for patients with SCTC.
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Adenocarcinoma Folicular/mortalidade , Carcinoma Papilar/mortalidade , Carcinoma/mortalidade , Neoplasias da Glândula Tireoide/mortalidade , Adulto , Idoso , Estudos de Coortes , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Análise de Regressão , Programa de SEER , Câncer Papilífero da TireoideRESUMO
The treatment of papillary thyroid microcarcinoma (PTMC) remains deeply controversial. In this study, we investigated the prognosis of patients who underwent biopsy alone, as compared with other forms of thyroidectomy approaches. We sought to provide reference information for treatment selection in cases of PTMC.The analysis included a large cohort of 34,972 PTMC patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2013. Survival was examined by Kaplan-Meier analyses with log-rank tests, Cox proportional-hazards regression analyses, and propensity score matching analyses.In the study cohort, the rate of cancer-specific mortality per 1000 person-years was higher for patients who underwent biopsy alone than for those who underwent other surgical approaches. According to multivariate Cox regression analyses, patients undergoing biopsy had similar cancer-specific survival rates and higher all-cause survival rates in comparison with patients undergoing other surgical approaches. After matching for influential factors using propensity scores, Kaplan-Meier analyses also showed that patients undergoing biopsy had similar cancer-specific survival rates and lower all-cause survival rates in comparison with patients undergoing other surgical approaches.Our results provided helpful implications for the treatment of patients with PTMC.
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Biópsia/métodos , Carcinoma Papilar/patologia , Carcinoma Papilar/cirurgia , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/cirurgia , Tireoidectomia/métodos , Adulto , Fatores Etários , Idoso , Carcinoma Papilar/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Pontuação de Propensão , Análise de Regressão , Programa de SEER , Fatores Sexuais , Neoplasias da Glândula Tireoide/mortalidadeRESUMO
In differentiated thyroid cancer (DTC), TX stage is defined as 'primary tumour cannot be assessed'. The prognosis of patients with TX stage remains unclear. The aim of this study was to investigate the prognosis of TX stage and provide a perspective on treatment guidelines. We investigated a large cohort of DTC patients from the Surveillance, Epidemiology, and End Results database between 2004 and 2013. Patient mortality was examined by Kaplan-Meier analyses with log-rank tests and Cox proportional hazards regression analyses. The rate of cancer-specific mortality per 1000 person-years for patients with TX stage was higher than for patients with T1-T3 stage, but lower than for patients with T4 stage. The all-cause mortality per 1000 person-years for TX stage patients was also higher than for T1-T3 stage patients, but lower than for T4 stage patients. TX stage showed significant risk for cancer-specific mortality compared to T1 and T4 stages, but not T2 and T3 stages, after adjusting for influential risk factors. TX stage patients showed no significant risk for all-cause mortality compared to T2-T3 stage patients, but were different than T1 and T4 stage patients. These results provide new implications for the treatment of TX stage DTC patients.
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[This corrects the article DOI: 10.18632/oncotarget.21242.].
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[This corrects the article DOI: 10.18632/oncotarget.20732.].
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[This corrects the article DOI: 10.18632/oncotarget.19988.].
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Few studies have evaluated the prognosis or treatment of patients with differentiated thyroid cancer (DTC) according to their NX status. This study investigated this issue to provide a new perspective regarding the treatment guidelines for these patients. Data from 92,447 patients with DTC were obtained from the Surveillance, Epidemiology, and End Results (SEER) database (2004-2013). Survival outcomes were evaluated using Kaplan-Meier analyses with the log-rank test and Cox proportional hazards regression analysis. The rates of cancer-specific mortality and all-cause mortality (per 1,000 person-years) were significantly higher for patients with NX disease, compared to patients with N0 or N1 disease. Multivariate Cox regression modeling revealed that NX stage was an independent risk factor for cancer-specific mortality compared to N1 stage, but not to N0 stage. Similar results were observed for all-cause mortality. After adjustment using propensity score matching, the cancer-specific and all-cause mortality rates were lower for NX stage compared to N0 stage, whereas no significant difference was observed when comparing the NX stage and N1 stage groups. The unexpectedly poor prognosis of patients with NX stage DTC provides new information that may be relevant for treating these patients.
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There is controversy regarding the prognosis of patients with oxyphilic thyroid cancer (OXTC). The present study compared the prognoses of OXTC, papillary thyroid cancer (PTC), and follicular thyroid cancer (FTC), in order to provide a new perspective regarding the treatment guidelines for these diseases. We evaluated data from patients with thyroid cancer who were included in the Surveillance, Epidemiology, and End Results database between 2004 and 2013. Patient mortality was evaluated using Cox proportional hazards regression analyses and Kaplan-Meier analyses with log-rank tests. The multivariate Cox regression analysis revealed that the cancer-specific survival rate for OXTC was similar to that for PTC, but higher than that for FTC. However, after propensity score matching for relevant factors, the cancer-specific survival rate for OXTC was higher than that for PTC and FTC. This unexpected result provides new implications for the treatment of patients with OXTC.
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Insular thyroid carcinoma (ITC) is an uncommon thyroid malignancy with an unclear prognosis. The aim of this study was to determine the prognoses of patients with ITC. We investigated a large cohort of patients with differentiated thyroid cancer from the Surveillance, Epidemiology, and End Results (SEER) database who were registered between 2004 and 2013, and compared the prognosis of patients with ITC to those with classic papillary thyroid cancer (CPTC) and follicular thyroid cancer (FTC). Patient mortality was determined using Kaplan-Meier analyses with log-rank tests, as well as Cox proportional hazards regression analyses. The study cohort comprised of 165 patients with ITC, 5419 patients with FTC, and 60739 patients with CPTC. The rate of cancer-specific mortality per 1000 person-years for ITC was higher than that for CPTC or FTC. According to multivariate Cox regression analysis, however, the cancer-specific and all-cause mortality rates of ITC were similar to those of CPTC and FTC. The cancer-specific survival rate in patients with ITC was higher than that in patients with CPTC, but similar to that in patients with FTC, after adjusting for potentially influencing factors using propensity score matching analysis. These findings, which contrast with previously published data, provide new implications for the treatment of patients with ITC.
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The prognosis of patients with mixed subtype thyroid cancer (MSTC) is unclear. The present study compared the prognoses of MSTC, papillary thyroid cancer (PTC), and follicular thyroid cancer (FTC) to provide a new perspective regarding the treatment guidelines for these diseases. We evaluated data from patients with thyroid cancer who were included in the Surveillance, Epidemiology, and End Results database between 2004 and 2013. Patient mortality was evaluated using Cox proportional hazards regression analyses and Kaplan-Meier analyses with log-rank tests. The univariate Cox regression analysis showed that the cancer-specific survival rate for MSTC was lower than that for PTC and FTC. However, in the multivariate Cox regression analysis, the cancer-specific survival rate for MSTC was similar to that for PTC and FTC. Before matching influence factors, the cancer-specific survival rate for MSTC was lower than that for PTC and FTC. However, after propensity score matching for relevant factors, the cancer-specific survival rate for MSTC was also similar to that for PTC and FTC. Our result would be beneficial and provide a guideline for the understanding of MSTC.
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The prognosis of oxyphilic cell papillary thyroid carcinoma (OCPTC) remains unclear. The aim of this study was to investigate the prognosis of OCPTC and provide a new perspective on treatment guidelines for these patients. We investigated a large cohort of DTC patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2013. Patient mortality was examined by Kaplan-Meier analyses with log-rank tests and Cox proportional hazards regression analyses. In the study cohort, the rate of cancer-specific mortality per 1000 person-years for OCPTC was lower than that for classic papillary thyroid cancer (CPTC) and follicular thyroid cancer (FTC). According to the multivariate Cox regression model, the cancer-specific and all-cause mortality rates of OCPTC were similar to that of CPTC and FTC. The cancer-specific survival rate in patients with OCPTC was higher than that in patients with FTC, but similar to patients with CPTC, after matching for influential factors using propensity score matching analysis. The unanticipated prognosis provided new implications for the treatment of patients with OCPTC.
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The prognosis of T0 stage differentiated thyroid cancer (DTC) remains unclear. This study aimed to investigate the prognosis of T0 stage DTC patients to provide a new perspective on treatment guidelines for these patients. We investigated a large cohort of DTC patients from the Surveillance, Epidemiology, and End Results (SEER) database between 2004 and 2013. Patient survival curves were examined by Kaplan-Meier analyses with log-rank tests and Cox proportional hazards regression analyses. In the study cohort, the rate of cancer-specific mortality per 1000 person-years for T0 was higher than T1-T3, but lower than T4. The all-cause mortality for T0 patients was higher than all other stages (T1-T4). Multivariate Cox regression modeling showed that T0 had a significant risk for cancer-specific mortality when compared to T1 and T4, but not T2 or T3, after adjustment for other risk factors. For all-cause mortality, T0 showed a significant risk for all-cause mortality when compared to T4, but not T1-T3 stage patients. Similar results were obtained after matching for influential factors using propensity scored matching analysis. The unanticipated prognosis of T0 stage DTC patients was found to be not better than of other stage DTC patients, providing new implications for the treatment of T0 stage DTC patients.