Identification of Serpin peptidase inhibitor clade A member 1 (SERPINA1) might be a poor prognosis biomarker promoting the progression of papillary thyroid cancer.

BACKGROUND: Papillary thyroid carcinoma (PTC) is the most prevalent malignancy within the endocrine system, exhibiting a rapid growth rate in recent years. Serpin peptidase inhibitor clade A member 1 (SERPINA1) has been previously proposed as a diagnostic biomarker; however, it's potential molecular relevance and biological function in PTC remains largely unexplored. METHODS: Our study utilized multi-omics bioinformatic data from several public databases, supplemented with transcriptional profiles using our local cohort comprising 79 paired PTC samples. RESULTS: Using multi-omics profiling of a PTC cohort, we have identified SERPINA1 as a potential oncogene involved in PTC progression. Our clinical analysis revealed a significant association between SERPINA1 expression and mutations in BRAFV600E and RAS. Furthermore, SERPINA1 level was correlated with clinicopathological factors in patients with PTC and with a worse prognosis in early-stage patients. Functionally, we found a strong correlation between SERPINA1 expression and increased infiltration of dendritic cells and regulatory T-cells, suggesting an elevated level of immune infiltration. Moreover, SERPINA1 knockdown reduced the proliferative and migrational ability of PTC cells in vitro. CONCLUSION: Our study highlights the high expression of SERPINA1 in PTC and its potential role in shaping the immune microenvironment, thereby promoting disease progression. These findings suggest that SERPINA1 could serve as a promising therapeutic target for intervention in PTC.

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

bub1 as a potential oncogene and a prognostic biomarker for neuroblastoma.

Background: Neuroblastoma is the most common malignant extracranial tumor for children. Molecular mechanisms underpinning the pathogenesis of this disease are yet to be fully clarified. This study aimed to identify a novel oncogene that could be used as a biomarker informing the prognosis of neuroblastoma, and to predict its biological functions, using bioinformatics and molecular biology tools. Methods: Three data sets from the TARGET, GSE62564, and GSE85047 databases were used for analysis. Survivals of patients with high or low expression of bub1 were compared, using the Kaplan-Meier curve and log-rank test. Immune infiltration was evaluated using ESTIMATE and MCP-counter algorithms. Synthetic small interfering RNAs (siRNAs) were employed to silence bub1 expression in neuroblastoma cell lines SH-SY5Y and SK-N-SH, in order to characterize its biological functions. Gene enrichment analyses of bub1 were carried out, using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Results: Expression of bub1 was found to significantly affect overall survival and event-free survival of patients with neuroblastoma, positively correlate with the expressions of tpx2 and the ASPM gene, and negatively correlate with host immune infiltration. Expression of bub1 was elevated in patients with neuroblastoma. Silencing bub1 expression using siRNAs in SH-SY5Y and SK-N-SH resulted in decreased cell growth (p < 0.05), reduced migration (p < 0.05), and increased apoptosis (p < 0.05). Function analysis of bub1 revealed cancer-promoting effects, probably via regulating several important downstream molecules, including that related to the apoptosis process and epithelial-mesenchymal transition. Conclusion: We identified a potential tumor-promoting gene bub1 for neuroblastoma that could also serve as a prognostic biomarker.

Overexpression of PKMYT1 associated with poor prognosis and immune infiltration may serve as a target in triple-negative breast cancer.

Breast cancer (BC) is one of the most common malignancies among women worldwide. It is necessary to search for improvement in diagnosis and treatment methods to improve the prognosis. Protein kinase, membrane associated tyrosine/threonine 1 (PKMYT1), a member of the Wee family of protein kinases, has been studied in some tumors except BC. This study has explored that PKMYT1 functional role by bioinformatics methods combined with local clinical samples and experiments. Comprehensive analysis showed that PKMYT1 expression was higher in BC tissues, especially in advanced patients than that in normal breast tissues. The expression of PKMYT1 was an independent determinant for BC patients' prognosis when combined with the clinical features. In addition, based on multi-omics analysis, we found that the PKMYT1 expression was closely relevant to several oncogenic or tumor suppressor gene variants. The analysis of single-cell sequencing indicated that PKMYT1 expression was upregulated in triple-negative breast cancer (TNBC), consistent with the results of bulk RNA-sequencing. High PKMYT1 expression was correlated with a poor prognosis. Functional enrichment analysis revealed that PKMYT1 expression was associated with cell cycle-related, DNA replication-related, and cancer-related pathways. Further research revealed that PKMYT1 expression was linked to immune cell infiltration in the tumor microenvironment. Additionally, loss-of-function experiments in vitro were performed to investigate the role of PKMYT1. TNBC cell lines' proliferation, migration, and invasion were inhibited when PKMYT1 expression was knock-down. Besides, the down-regulation of PKMYT1 induced apoptosis in vitro. As a result, PKMYT1 might be a biomarker for prognosis and a therapeutic target for TNBC.

VX765 alleviates dextran sulfate sodium-induced colitis in mice by suppressing caspase-1-mediated pyroptosis.

Inflammatory bowel disease (IBD) is an autoimmune disease involving intestinal tissue. IBD activates a series of cell death pathways. Pyroptosis is recently identified as a critical cell death pathway in IBD associated with the activation of caspase-1. VX765 is a caspase-1 inhibitor that can be converted to VRT-043198 in vivo. This study was designed to explore the therapeutic effect of VX765 on colitis using a dextran sulfate sodium (DSS)-induced colitis model in mice. In this research, the caspase-1 inhibitor on inflammatory, pyroptosis, apoptosis, macrophage activation, and intestinal barrier were investigated. We found that administration of VX765 attenuated body weight loss, colonic shortening, and colonic pathological injury in mice. Our study also revealed a therapeutic effect of VX765 on colitis in a dose-dependent manner. VX765 inhibited pyroptosis by curbing the Caspase-1/GSDMD pathway and its downstream key inflammatory cytokines--IL-1ß and IL-18. These results indicated that VX765 might have a dose-dependent therapeutic effect on DSS-induced colitis in mice.

Genomic Instability-Related LncRNA Signature Predicts the Prognosis and Highlights LINC01614 Is a Tumor Microenvironment-Related Oncogenic lncRNA of Papillary Thyroid Carcinoma.

BACKGROUND: Genomic instability (GI) is among the top ten characteristics of malignancy. Long non-coding RNAs (lncRNAs) are promising cancer biomarkers that are reportedly involved in GI. So far, the clinical value of GI-related lncRNAs (GIlncs) in papillary thyroid cancer (PTC) has not been clarified. METHODS: Integrative analysis of lncRNA expression and somatic mutation profiles was performed to identify GIlncs. Analysis of differentially expressed lncRNAs in the group with high- and low- cumulative number of somatic mutations revealed significant GIlncs in PTC. Univariate and multivariate Cox proportional hazard regression analyses were performed to identify hub-GIlncs. RESULTS: A computational model based on four lncRNAs (FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1) was identified as a quantitative index using an in-silicon discovery cohort. GILS score was significantly associated with poor prognosis, as validated in the TCGA dataset and further tested in our local RNA-Seq cohort. Moreover, a combination of clinical characteristics and the composite GILS-clinical prognostic nomogram demonstrates satisfactory discrimination and calibration. Furthermore, the GILS score and FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1 were also associated with driver mutations and multiple clinical-pathological variables, respectively. Moreover, RNA-Seq confirmed the expression patterns of FOXD2-AS1, LINC01614, AC073257.2, and AC005082.1 in PTC and normal thyroid tissues. Biological experiments demonstrated that downregulated or overexpressed LINC01614 affect PTC cell proliferation, migration, and invasion in vitro. Activation of the stromal and immune cell infiltration was also observed in the high LINC01614 group in the PTC microenvironment. CONCLUSION: In summary, we identified a signature for clinical outcome prediction in PTC comprising four lncRNAs associated with GI. A better understanding of the GI providing an alternative evaluation of the progression risk of PTC. Our study also demonstrated LINC01614 as a novel oncogenic lncRNA and verified its phenotype in PTC.

Pan-cancer analysis of the prognostic and immunological role of PSMB8.

Recently some evidence has demonstrated the significance of PSMB8 in various malignancies. Nevertheless, PSMB8 (proteasome subunit beta 8), more familiar in the field of immunology contributing to the process of antigen presentation, is indeterminate in the role as a survival predictor of human pan-cancer. Besides, how PSMB8 interacts with immune cell infiltration in the tumor microenvironment requires further research. We then penetrated into the analysis of the PSMB8 expression profile among 33 types of cancer in the TCGA database. The results show that overexpression of PSMB8 was associated with poor clinical outcomes in overall survival (Sartorius et al. in Oncogene 35(22):2881-2892, 2016), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI) in most cancer varieties. In addition, there existed distinctly positive correlations between PSMB8 and immunity, reflected straightforwardly in the form of immune scores, tumor-infiltrating immune cells (TIICs) abundance, microsatellite instability, tumor mutation burden, and neoantigen level. Notably, specific markers of dendrite cells exhibited the tightest association with PSMB8 expression in terms of tumor-related immune infiltration patterns. Moreover, gene enrichment analysis showed that elevated PSMB8 expression was related to multiple immune-related pathways. We finally validated the PSMB8 expression in our local breast samples via quantitative PCR assays and concluded that PSMB8 appeared to perform well in predicting the survival outcome of BRCA patients. These findings elucidate the pivotal role of the antigen presentation-related gene PSMB8, which could potentially serve as a robust biomarker for prognosis determination in multiple cancers.

L Antigen Family Member 3 Serves as a Prognostic Biomarker for the Clinical Outcome and Immune Infiltration in Skin Cutaneous Melanoma.

L Antigen Family Member 3 (LAGE3) is an important RNA modification-related protein. Whereas few studies have interrogated the LAGE3 protein, there is limited data on its role in tumors. Here, we analyzed and profiled the LAGE3 protein in skin cutaneous melanoma (CM) using TCGA, GTEx, or GEO databases. Our data showed an upregulation of LAGE3 in melanoma cell lines compared to normal skin cell lines. Besides, the Kaplan-Meier curves and Cox proportional hazard model revealed that LAGE3 was an independent survival indicator for CM, especially in metastatic CM. Moreover, LAGE3 was negatively associated with multiple immune cell infiltration levels in CM, especially CD8+ T cells in metastatic CM. Taken together, our study suggests that LAGE3 could be a potential prognostic biomarker and might be a potential target for the development of novel CM treatment strategies.

Major Vault Protein (MVP) Associated With BRAF V600E Mutation Is an Immune Microenvironment-Related Biomarker Promoting the Progression of Papillary Thyroid Cancer via MAPK/ERK and PI3K/AKT Pathways.

Papillary thyroid cancer (PTC) is the most common malignancy of the endocrine system, with an increase in incidence frequency. Major vault protein (MVP) is the main structural protein of the vault complex that has already been investigated in specific cancers. Yet the underlying biological functions and molecular mechanisms of MVP in PTC still remain considerably uncharacterized. Comprehensive analyses are predicated on several public datasets and local RNA-Seq cohort. Clinically, we found that MVP was upregulated in human PTC than in non-cancerous thyroid tissue and was correlated with vital clinicopathological parameters in PTC patients. MVP expression was associated with BRAF V600E, RAS, TERT, and RET status, and it was correlated with worse progression-free survival in PTC patients. Functionally, enrichment analysis provided new clues for the close relationship between MVP with cancer-related signaling pathways and the immune microenvironment in PTC. In PTC with high MVP expression, we found CD8+ T cells, regulatory T cells, and follicular helper T cells have a higher infiltration level. Intriguingly, MVP expression was positively correlated with multiple distinct phases of the anti-cancer immunity cycle. MVP knockdown significantly suppressed cell viability and colony formation, and promoted apoptosis. In addition, downregulated MVP markedly inhibited the migration and invasion potential of PTC cells. The rescue experiments showed that MVP could reverse the level of cell survival and migration. Mechanistically, MVP exerts its oncogenic function in PTC cells through activating PI3K/AKT/mTOR and MAPK/ERK pathways. These results point out that MVP is a reliable biomarker related to the immune microenvironment and provide a basis for elucidating the oncogenic roles of MVP in PTC progression.

Identification and validation of L Antigen Family Member 3 as an immune-related biomarker associated with the progression of papillary thyroid cancer.

BACKGROUND: Papillary thyroid cancer (PTC) is heterogeneous cancer with many different immune cells involved in its pathogenesis. L Antigen Family Member 3 (LAGE3) is an ESO/LAGE gene family member that has not been extensively studied in PTC. METHODS: Comprehensive bioinformatics analyses of LAGE3 were based on The Cancer Genome Atlas, Gene Expression Omnibus, and Genomics of Drug Sensitivity in Cancer (GDSC) databases. We also performed RNA-sequencing on 78 paired samples from local PTC patients. RESULTS: We observed that LAGE3 was significantly up-regulated in most solid tumor types, including PTC compared with corresponding normal tissues. The high level of LAGE3 was also significantly associated with advanced malignancy. LAGE3 expression was significantly associated with cancer-related pathways, biochemical metabolism, and immune-related terms. Further, tumor microenvironment analysis indicated LAGE3 was positively correlated with different immune cells infiltrating levels and the activity of different steps of the cancer-immunity cycle. Analyses based on the GDSC database revealed that low levels of LAGE3 might be resistant to WZ3105, I-BET-762, and PHA-793887. In addition, the experimental results validated that knocking down LAGE3 could affect proliferation, migration, and invasion in the PTC cell lines. CONCLUSION: This study discloses that LAGE3 plays an oncogenic and cancer-immunological role, also providing novel PTC biological and clinical implications.

Subcutaneous Recurrences of Thyroid Cancer After Conventional Transcervical Thyroidectomy: A Case Report.

Metastatic subcutaneous implantation of the follicular variant of papillary thyroid cancer is very rare. We present a 62-year-old woman with a history of follicular variant of papillary thyroid cancer, who developed multiple asymptomatic subcutaneous nodules, after 5 years of initial thyroidectomy. Eventually, the subcutaneous nodules were diagnosed as tumor recurrence and completely excised. She has reportedly lived for more than 1 year, without signs of disease progression or recurrence. This case emphasizes the need for surgeons to take into account the tumor-free concept during the operation, and to a great extent prevent the occurrence of implantation recurrence.

LAGE3 correlates with tumorigenic immune infiltrates in the clear cell renal cell carcinoma microenvironment.

OBJECTIVE: Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney tumor worldwide. The role of LAGE3 (L Antigen Family Member 3) in ccRCC has not been widely reported. In this study, we explored the clinical significances and biological functions of LAGE3 in ccRCC. METHODS: The RNA-seq data and the corresponding clinical information of the patients with ccRCC were extracted from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. ESTIMATE, quanTiseq, and xCell algorithms were used to estimate the immune infiltration levels in the ccRCC microenvironment. RESULTS: We found that overexpression of LAGE3 was associated with adverse clinical-pathological factors, and correlated with poor prognosis in multiple ccRCC cohorts. Multivariate analysis indicated that LAGE3 was an independent survival determinant in patients with ccRCC, whereas functional enrichment analysis suggested that LAGE3 may regulate humoral immune response, immunoglobulin complex, and receptor-ligand activity. Further, tumor microenvironment analysis based on different algorithms indicated LAGE3 was positively associated with the immune activity and infiltrating levels of different immune cells. Particularly, LAGE3 expression had a positive impact on different steps of the cancer-immunity cycle. CONCLUSION: The present findings disclose that LAGE3 could be an independent survival predictor, and might contribute to developing novel ccRCC immunological treatment strategies.

Upregulation of LAGE3 correlates with prognosis and immune infiltrates in colorectal cancer: A bioinformatic analysis.

BACKGROUND: Colorectal cancer (CRC) is the primary cause of cancer-related deaths worldwide. Identification of new CRC biomarkers is imperative to improve the prognosis and development of therapies against the disease. LAGE3 (L Antigen Family Member 3) functions as a tRNA modifier, although its potential role in CRC has not been fully elucidated. METHODS: RNA-seq matrix and corresponding clinical information were downloaded from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, then subjected to survival, enrichment, and tumor microenvironment analyses using packages implemented in R. RESULTS: We found that LAGE3 was upregulated and significantly correlating with poor prognosis in multiple CRC cohorts. Additionally, multivariate Cox regression analysis revealed that LAGE3 was an independent prognostic factor in patients with CRC, whereas functional enrichment analysis indicated that it could regulate protein targeting, tRNA processing, and the PD-1/PD-L1 checkpoint pathway. Furthermore, CIBERSORT analysis indicated a negative relationship between LAGE3 and levels of infiltration for multiple immune cells, especially CD8 + T cells in CRC. Particularly, LAGE3 expression was inversely correlated with the expression of immune checkpoints as well as that of various immune cell types of signature genes. CONCLUSION: Collectively, our results indicate that high LAGE3 expression correlates with adverse prognosis and poor immune infiltration in CRC patients.

Up-regulation of L Antigen Family Member 3 Associates With Aggressive Progression of Breast Cancer.

The role of L Antigen Family Member 3 (LAGE3) in breast cancer (BC) has not been sufficiently studied. In this study, we explored the clinical value and biological functions of LAGE3 in BC. Comprehensive analysis of LAGE3 was carried out on The Cancer Genome Atlas, Molecular Taxonomy of Breast Cancer International Consortium and Gene Expression Omnibus datasets. Results showed that LAGE3 expression was higher in BC tissues than in normal breast tissues of public datasets and our local cohort. Moreover, its expression was higher in BC patients with larger tumor size, significant lymph node metastasis, higher tumor grade, and more advanced disease stage. High expression of LAGE3 was correlated with poor prognosis, and LAGE3 could independently predict survival of BC patients. Functional enrichment analysis revealed a correlation between LAGE3 expression and biochemical metabolism and immune-related terms and cancer-related pathways. Analysis of tumor microenvironment indicated that LAGE3 expression was associated with the immune cell infiltration and anti-cancer immunity cycle. LAGE3 expression was higher in triple-negative breast cancer (TNBC) compared to hormone receptor-positive BC, but not HER2-positive subtype. Suppression of LAGE3 expression inhibited the proliferation and induced apoptosis of TNBC cell lines. Besides, the down-regulation of LAGE3 attenuated the migration and invasion but reduced the expression level of epithelial-mesenchymal-transition related proteins in TNBC cell lines. In conclusion, this study demonstrated for the first time that LAGE3 promotes the progression of BC. Therefore, it may be a potential diagnostic and prognostic biomarker, as well as a treatment target for BC.

Exploration of the Prognostic and Immunotherapeutic Value of B and T Lymphocyte Attenuator in Skin Cutaneous Melanoma.

B and T lymphocyte attenuator (BTLA) is a newly identified immune checkpoint molecular belonging to the CD28 immunoglobulin superfamily. However, the expression and clinical value of BTLA in skin cutaneous melanoma (SKCM) has not been widely characterized. We found that BTLA levels were upregulated in metastatic melanoma compared to normal skin tissues and primary melanoma. Higher BTLA was also correlated with improved prognosis in SKCM based on several datasets. The multivariate Cox regression model revealed that BTLA was an independent survival indicator in metastatic melanoma. Tumor microenvironment analysis indicated BTLA was positively associated with the infiltrating levels of different immune cells and the activity of the anti-cancer immunity cycle. Importantly, BTLA accurately predicted the outcome of melanoma patients treated with MAGE-A3 blocker or first-line anti-PD-1. The present findings disclose that BTLA is a reliable biomarker for prognosis and immunotherapeutic response and might contribute to developing novel SKCM immunological treatment strategies.

T-Box Transcription Factor 22 Is an Immune Microenvironment-Related Biomarker Associated With the BRAF V600E Mutation in Papillary Thyroid Carcinoma.

Papillary thyroid cancer (PTC) is the most common malignant disease in endocrine systems. T-box transcription factor 22 (TBX22) is a phylogenetically conserved family member that has not been widely characterized in cancers. In this study, we explored the potential clinical significance and biological functions of TBX22 in PTC. Comprehensive analyses of TBX22 were based on the public databases and our local qRT-PCR cohort. We observed that TBX22 was significantly downregulated in PTC compared with normal tissues. TBX22 was associated with several clinicopathological factors in PTC. Low TBX22 expression correlated with BRAF V600E and TERT mutation. Functional enrichment analysis revealed that cancer-related pathways and immune progress were closely associated with TBX22 in PTC. In TBX22-low PTC, high immune infiltration levels with increased CD8+ T cells, natural killer, M1 macrophages, and T-regulatory cells were observed. TBX22 was negatively correlated with the activity of different steps of the anticancer immunity cycle. Functionally, overexpression of TBX22 inhibited the proliferation, invasion, and migration in PTC cells, while knocking down of TBX22 showed the opposite effects. The present findings disclose that TBX22, as an immune microenvironment-related biomarker, could be an important tumor suppresser gene and might inform the management of PTC patients better.