Progression-free Interval Research Articles

Based on different immune responses under the glucose metabolizing type of papillary thyroid cancer and the response to anti-PD-1 therapy.

Glucose metabolism-related genes play an important role in the development and immunotherapy of many tumours, but their role in thyroid cancer is ambiguous. To investigate the role of glucose metabolism-related genes in the development of papillary thyroid cancer (PTC) and their correlation with the clinical outcome of PTC, we collected transcriptomic data from 501 PTC patients in the Cancer Genome Atlas (TCGA). We performed nonnegative matrix decomposition clustering of 2752 glucose metabolism-related genes from transcriptome data and classified PTC patients into three subgroups (C1 for high activation of glucose metabolism, C2 for low activation of glucose metabolism and C3 for moderate activation of glucose metabolism) based on the activation of different glucose metabolism-related genes in 10 glucose metabolism-related pathways. We found a positive correlation between the activation level of glucose metabolism and the tumour mutation burden (TMB), neoantigen number, mRNA stemness index (mRNAsi), age, and tumour stage in PTC patients. Next, we constructed a prognostic prediction model for PTC using six glucose metabolism-related genes (PGBD5, TPO, IGFBPL1, TMEM171, SOD3, TDRD9) and constructed a nomogram based on the risk score and clinical parameters of PTC patients. Both the prognostic risk prediction model and nomogram had high stability and accuracy for predicting the progression-free interval (PFI) in PTC patients. Patients were then divided into high-risk and low-risk groups by risk score. The high-risk group was sensitive to paclitaxel and anti-PD-1 treatment, and the low-risk group was sensitive to sorafenib treatment. We found that the high-risk group was enriched in inflammatory response pathways and associated with high level of immune cell infiltration. To verify the accuracy of the prognostic prediction model, we knocked down PGBD5 in PTC cells and found that the proliferation ability of PTC cells was significantly reduced. This suggests that PGBD5 may be a relatively important oncogene in PTC. Our study constructed a prognostic prediction model and classification of PTC by glucose metabolism-related genes, which provides a new perspective on the role of glucose metabolism in the development and immune microenvironment of PTC and in guiding chemotherapy, targeted therapy and immune checkpoint blockade therapy of PTC.

Integrated genomic, transcriptomic, and epigenetic analyses identify a leukotriene synthesis-related M2 macrophage gene signature that predicts prognosis and treatment vulnerability in gliomas.

The pathological implications of tumor-associated macrophages in the glioma microenvironment have been highlighted, while there lacks a gene signature to characterize the functional status and clinical implications of these cells. Comprehensive bioinformatics approaches were employed to develop an M2 macrophage-associated gene signature at bulk-tumor and single-cell levels and explore immunological and metabolic features. Consequently, the PI3K pathway and fatty acid metabolism were correlated with the M2 fraction. Further distilling the pathway members resulted in a leukotriene synthesis-related gene signature (Macro index), including PIK3R5, PIK3R6, ALOX5, ALOX5AP, and ALOX15B, that was primarily expressed by monocytes/macrophages. Increased Macro index predicted IL13-induced macrophages, and was associated with T-cell dysfunction at both transcriptional and epigenetic levels and predicted an unfavorable outcome. Besides, the Macro index was proportional with PAI1 at the protein level, with high levels of the latter suggesting a decreased progression-free interval of glioblastoma. Notably, the monocytes/macrophages in the glioma environment contribute to the expression of immune checkpoints and the Macro index predicts glioma responsiveness to anti-PD1 treatment. Together, our study proposed a leukotriene synthesis-related M2 macrophage gene signature, which may provide insights into the role of these cells in the glioma microenvironment and facilitate individually tailored therapeutic strategies for the disease.

Safety and efficacy of RFA versus MWA for T1a renal cell carcinoma: a propensity score analysis

ObjectivesPercutaneous radiofrequency ablation (RFA) is stated as a treatment option for renal cell carcinoma (RCC) smaller than 4 cm (T1a). Microwave ablation (MWA) is a newer technique and is still considered experimental in some guidelines. The objective of this study was to compare the safety and efficacy of RFA and MWA for the treatment of RCC.MethodsPatients with T1a RCC treated by RFA or MWA in two referral centers were retrospectively analyzed. Patient records were evaluated to generate mRENAL nephrometry scores. Local tumor progression (LTP) was considered when new (recurrence) or residual tumor enhancement within/adjacent to the ablation zone was objectified. Differences in LTP-free interval (residual + recurrence) between ablation techniques were assessed with Cox proportional hazards models and propensity score (PS) methods.ResultsIn 164 patients, 87 RFAs and 101 MWAs were performed for 188 RCCs. The primary efficacy rate was 92% (80/87) for RFA and 91% (92/101) for MWA. Sixteen patients had residual disease (RFA (n = 7), MWA (n = 9)) and 9 patients developed recurrence (RFA (n = 7), MWA (n = 2)). LTP-free interval was significantly worse for higher mRENAL nephrometry scores. No difference in LTP-free interval was found between RFA and MWA in a model with inverse probability weighting using PS (HR = 0.99, 95% CI 0.35–2.81, p = 0.98) and in a PS-matched dataset with 110 observations (HR = 0.82, 95% CI 0.16–4.31, p = 0.82). Twenty-eight (14.9%) complications (Clavien-Dindo grade I–IVa) occurred (RFA n = 14, MWA n = 14).ConclusionPrimary efficacy for ablation of RCC is high for both RFA and MWA. No differences in efficacy and safety were observed between RFA and MWA.Key Points• Both RFA and MWA are safe and effective ablation techniques in the treatment of T1a renal cell carcinomas.• High modified RENAL nephrometry scores are associated with shorter local tumor progression-free interval.• MWA can be used as heat-based ablation technique comparable to RFA for the treatment of T1a renal cell carcinomas.

High expression of glycolysis-related PGM2 gene in relation to poor prognosis and deficient immune cells infiltration in lung adenocarcinoma: a study based on bioinformatics analysis.

BackgroundLung adenocarcinoma (LUAD) is the most important subtype of lung cancer and usually metastasizes. Patients with LUAD usually had a poor prognosis. Identifying viable molecular markers for diagnostic and prognostic prediction among individuals with LUAD is critical for the future management of this disease. This study aimed to determine and verify a correlation between the glycolysis-related phosphoglucomutase 2 (PGM2) gene and dissatisfactory results and deficient infiltration of immune cells in LUAD.MethodsThe expression of PGM2 in LUAD and adjoining normal tissues was screened from The Cancer Genome Atlas (TCGA) data and human protein atlas (HPA), and validatied by quantative reverse transcription polymerase chain reaction (qRT-PCR). We examined the correlation between PGM2 expression and clinicopathologic characteristics (including pathological stage, gender, M stage, smoker, age, N stage, race, and number pack years smoked) by multivariable approaches and Kaplan-Meier survival curves. The proteins network with PGM2 was built using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The correlation between PGM2 expression and infiltration of immune cells, along with the corresponding gene marker sets, was investigated through the Gene Expression Profiling Interactive Analysis (GEPIA) and Tumor Immune Estimation Resource (TIMER) databases. We evaluated the possible correlation between PGM2 expression and progression-free interval (PFI), disease-specific survival (DSS), and overall survival (OS) in LUAD patients.ResultsExpression of PGM2 was up-regulated in LUAD tissues (P=0.003). According to the multivariate logistic regression analysis, the elevated expression level of PGM2 exhibited a remarkable correlation with advanced tumor-node-metastasis (TNM) stage, high-grade malignancy, and primary therapeutic outcome . Overexpression of PGM2 was shown to be correlated with an unfavorable prognosis including OS (P=0.004, HR =1.54), DSS (P=0.003, HR =1.77), and PFI (P=0.003, HR =1.5) in LUAD. The proteins PGM1 and UGP2 were shown to have a significant correlation with PGM2. Additionally, PGM2 was associated with the lack of infiltrating immune cells as well as their associated gene marker sets in LUAD.ConclusionsOverexpression of PGM2 was shown to be associated with the progression and an unfavorable prognosis of LUAD, as well as with inefficient immune cell infiltration. PGM2 was expected to be a potential biological marker for predicting the prognosis of patients with LUAD.

Pan-cancer analysis identifies YTHDF2 as an immunotherapeutic and prognostic biomarker.

Background: N6-methyladenosine (m6A) modification is a dynamic and reversible post-transcriptional RNA modification prevalent in eukaryotic cells. YT521-B homology domain family 2 (YTHDF2) has been identified as a member of m6A reader protein involving in many vital biological processes, whereas its role and functional mechanisms in cancers remain unclear. Methods: Bioinformatics analyses were performed on multiple databases including GTEx, TCGA, GEO and Cbioportal to explore the connection between YTHDF2 expression and its genomic changes including tumor mutation burden, microsatellite instability and mismatch repair in 33 different cancer types. We also investigated the association of YTHDF2 expression with prognosis, immune infiltration, tumor microenvironment, immune checkpoints and chemokines. Besides, the correlation of YTHDF2 expression with copy number variation and promoter methylation was also studied in tumors compared with normal tissues. At last, we analyzed the protein-protein interacting network and related genes of YTHDF2 to enrich its potential functional mechanism in tumor development and progression. Real-time qPCR was used to verify the expression of YTHDF2-related genes in colorectal cancer cells, and immunohistochemical staining was adopted to verify immune infiltration in tissue sections from 51 hepatocellular carcinoma patients. Results: YTHDF2 was overexpressed in a majority of tumor types and associated with their poor overall survival, progression-free interval, and disease-specific survival. The correlation of YTHDF2 expression with tumor mutation burden, microsatellite instability and mismatch repair was also detected in most of the tumor types. Moreover, YTHDF2 might participate in the immune regulation through influencing the expression of immune checkpoint genes and the infiltration of immunocytes in tumor microenvironment. Notably, we demonstrated a positive correlation between YTHDF2 expression and the infiltration of CD8+ T cells and macrophages in many tumors, and it was verified in 51 clinic hepatocellular carcinoma tissues. In addition, the involvement of YTHDF2 in “Spliceosome” and “RNA degradation” were two potential functional mechanisms underlying its influence on tumor progression. The regulation of YTHDF2 on predicted genes has been verified in CRC cells. Conclusion: YTHDF2 might be a new therapeutic target and a potential biomarker of cancer immune evasion and poor prognosis.

The Clinical Value of Long Noncoding RNA DDX11-AS1 as a Biomarker for the Diagnosis and Prognosis of Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is a high-mortality malignant tumor with genetic and phenotypic heterogeneity, making predicting clinical outcomes challenging. The purpose of this investigation was to examine the potential usefulness of lncRNA DDX11 antisense RNA 1 (DDX11-AS1) as a biomarker for diagnosis and prognosis in hepatocellular carcinoma (HCC). The TCGA-LIHC datasets were searched for patients' clinical information and RNA-seq data, which were then collected. Relative expression levels of DDX11-AS1 in HCC tissues were determined by qRT-PCR. In order to test the sensitivity and specificity of the DDX11-AS1 receiver, receiver operating characteristic curves were utilized. The association of DDX11-AS1 expression with clinicopathological factors or prognosis was statistically analyzed. We found that the levels of DDX11-AS1 were higher in HCC specimens than in normal specimens. ROC analysis showed that DDX11-AS1 was a useful marker for discriminating HCC tissues from normal nontumor specimens. According to the results of clinical tests, a high level of DDX11-AS1 expressions was significantly related to the pathologic stage (p=0.015) and the histologic grade (p < 0.001). Survival studies indicated that patients with higher DDX11-AS1 expression had a significantly poorer overall survival (p=0.005) and progression-free interval (p=0.003) than those with lower DDX11-AS1 expression. Multivariate survival analysis verified that DDX11-AS1 expression level was an independent predictor for HCC patients. Overall, DDX11-AS1 may serve as a tumor promotor during HCC progression, and its high level may be a potential marker for HCC patients.

Clinical implication and immunological landscape analyses of ANLN in pan-cancer: A new target for cancer research.

Anillin is a F-actin binding protein (ANLN) mainly involved in the process of cytokinesis and known to be dysregulated in diverse cancers. However, the role of ANLN in pan-cancer prognosis and tumor immunity remains unclear. Gene expression profiles of 31 solid tumors were downloaded from The Cancer Genome Atlas (TCGA) database. ANLN mRNA and protein expression were quantified using quantitative real-time PCR (qRT-PCR) and immunohistochemistry (IHC). Protein expression of ANLN was further confirmed in Human Protein Atlas (HPA) database. Cox regression and Kaplan-Meier analysis were utilized to assess the prognostic value of ANLN in pan-cancer. The correlation between ANLN and different immune gene markers and infiltration cells was analyzed via ESTIMATE and CIBERSORT. A BLCA immunotherapy cohort: IMvigor (210) was used to confirm the role of ANLN in immune response. ANLN upregulation was detected in 21 types of cancers and was associated with poor overall survival (OS), disease-free interval (DFI), and progression-free interval (PFI) in most cancers except in THYM (Thymoma). Additionally, correlation analysis revealed a significantly positive association between ANLN expression and tumor mutation burden (TMB), microsatellite instability (MSI), immune cells infiltration. and immune checkpoint genes in various cancers. The BLCA immunotherapy cohort confirmed that patients with higher ANLN level had better immune responses and longer OS. ANLN may serve as a prognostic biomarker for pan-cancer. ANLN upregulation is associated with higher TMB, MSI, and immune cell infiltration in multiple types of tumors, shedding new light for cancer treatment.

Phospholipase A/acyltransferase 4 is a prognostic biomarker and correlated with immune infiltrates in pancreatic cancer

BackgroundPhospholipase A/acyltransferase (PLAAT) family exhibits O- and N-acyltransferase activity and biosynthesize N-acylated ethanolamine phospholipids. Previously, PLAAT4 was seen as a tumor suppressor, but the exact function of PLAAT4 in pancreatic cancer was still unknown. In this study, we investigated the relationship of PLAAT4 and pancreatic cancer. MethodsUsing the data from the cancer genome atlas (TCGA), Genotype-Tissue Expression (GTEx) database and Gene Expression Omnibus (GEO) datasets we compared the expression of PLAAT4 in normal and tumor tissues and analyzed the connections between PLAAT4 and several clinicopathological factors. Further, we conducted Gene ontology (GO) analysis, Gene set enrichment analysis (GSEA), single sample gene set enrichment analysis (ssGSEA) and estimate analysis to explore the association between PLAAT4 and biological function and immune infiltration. In addition, Kaplan-Meier (KM) analysis, univariate and multivariate Cox analysis were used to explore the association between PLAAT4 and prognosis. In addition, we plotted a nomogram according to the multivariate cox analysis visualizing the predictive ability of PLAAT4 on prognosis. In addition, we explore the influence of PLAAT4 on malignant behaviors of the pancreatic cancer cells in vitro. ResultsAfter comparing the expression of PLAAT4 in normal and tumor tissues, we found that the expression of PLAAT4 was significantly high in pancreatic ductal adenocarcinoma (PDAC) samples. In addition, the results of GO and GSEA found that the expression of PLAAT4 was related to cell cycle checkpoints, M phase, regulation by p53, cell cycle mitotic and etc. Further, ssGSEA has shown that PLAAT4 was positively related to the abundance of aDC, Th1 cells, Th2 cells and negatively related to the Th17 cells. Subsequently, KM analysis, univariate and multivariate Cox analysis were used to analyze the correlation between PLAAT4 and prognosis. Additionally, we found that higher expression of PLAAT4 was related to T stage, N stage, histologic grade, etc (P < 0.05) and has a significant correlation with poor Overall Survival (OS), Disease-Specific Survival (DSS) and Progression-Free Interval (PFI). At last, we proved that PLAAT4 contributed to the malignant behaviors of the pancreatic cancer cells. ConclusionThis study indicated PLAAT4 as a novel prognostic biomarker and an important molecular that mediated immune response in pancreatic cancer.

NT5E upregulation in head and neck squamous cell carcinoma: A novel biomarker on cancer-associated fibroblasts for predicting immunosuppressive tumor microenvironment.

Despite tremendous progress made in the diagnosis and managements, head and neck squamous cell carcinoma (HNSC) remains a global medical dilemma with dismal clinical prognosis and high mortality. Gene NT5E encodes the ecto-5’-nucleotidase (CD73), which facilitates the formation of immunosuppressive tumor microenvironment (TME) permissive for tumor progression in various malignancies. Nevertheless, the cell subsets NT5E expressed on and the potential function of NT5E in the TME of HNSC remain virgin lands in HNSC. In this study, we comprehensively performed integrated prognostic analysis and elucidated that NT5E was an independent prognostic indicator for HNSC, for which a high NT5E level predicted poor overall survival (OS), disease-specific survival (DSS) and progression-free interval (PFI) in HNSC patients (p<0.05). Enrichment analyses revealed the close correlation between NT5E and ECM remodeling, and the latent function of NT5E may involve in epithelial-to-mesenchymal transition (EMT) and metastasis during HNSC progression. HNSC-related immune infiltration analysis and single-cell type analysis demonstrated that NT5E expression was significantly positively associated with cancer-associated fibroblasts (CAFs) in HNSC (p<0.01). NT5E-related TME analysis revealed that NT5E-high group are characterized by low neoantigen loads (NAL, p<0.001) and tumor mutation burden (TMB, p<0.01), indicating high-NT5E-expression HNSC patients may be recalcitrant to immunotherapy. In-situ multicolor immunofluorescence staining was later conducted and the results further verified our findings. Taken together, NT5E could be a novel biomarker in HNSC. Predominantly expressed on CAFs, the upregulation of NT5E might predict an immunosuppressive TME for HNSC patients who may benefit little from immunotherapy. Targeting CAFs with high NT5E expression might be a novel therapeutic strategy for HNSC patients.

Increased expression of MMP17 predicts poor clinical outcomes in epithelial ovarian cancer patients.

Ovarian cancer has the highest fatality rate among female reproductive system cancers, which is due to lack of biomarker for diagnosis and prognosis. We aimed to evaluate the role of matrix metalloproteinase 17 (MMP17) in ovarian cancer tumorigenesis and prognosis. Based on the epithelial ovarian cancer (EOC) in The Cancer Genome Atlas database, we determined the expression of MMP17 using the Wilcoxon rank-sum test. The biological functions of MMP17 were evaluated using the Metascape database and Gene Set Enrichment Analysis. The association between MMP17 and immune cell infiltration was investigated by single sample Gene Set Enrichment Analysis. Logistic analysis was applied to study the correlation between MMP17 expression and clinicopathological characteristics. Finally, Cox regression analysis, Kaplan–Meier analysis, and nomograms were used to determine the predictive value of MMP17 on clinical outcomes in EOC patients. The expression of MMP17 was much higher in EOC patients than in pericarcinomatous tissues (P < .001). MMP17-associated differentially expressed genes were significantly enriched in cell extracellular matrix (ECM) degrading and corresponding pathways in the high MMP17 expression phenotype. MMP17 has a high sensitivity and specificity for EOC diagnosis, with an area under the curve of 0.988. MMP17 expression was found to be an independent risk factor for overall survival (hazard ratio [HR]: 1.488, P < .001), progression-free interval (HR: 1.347, P < .01), and disease-specific survival (HR: 1.548, P < .01). Increased MMP17 expression in EOC may contribute to carcinogenesis by degrading ECM and provide diagnostic and prognostic value for clinical outcomes.

The expression of POSTN and immune cell infiltration are prognostic factors of lung adenocarcinoma.

The objective of this study is to identify useful prognostic factors of lung adenocarcinoma (LUAD) by evaluating the changes of periostin (POSTN) expression activity and immune cell infiltration using public data repositories. The gene and protein expressions of POSTN in LUAD were collected and analyzed from Ualcan and Human Protein Atlas online database. The cell infiltration data of immune cells in LUAD patients were retrieved and processed using the TIMER tool. Cox regression analysis was employed to screen and characterize prognosis factors, Kaplan–Meier Plotter was used to analyze the survival curve of LUAD patients, and receiver operating characteristic curve was used to calculate the relationship between temporal POSTN expressions and the prognosis of LUAD. The expression activity of POSTN in LUAD was higher than that in normal tissues. With the exception of B cell which showed opposite correlationship, the infiltration of most immune cells, namely CD8+ T cells, macrophages, neutrophils, and dendritic cells, was positively correlated with the POSTN expression activity. Together, our investigation suggested that the POSTN expression activity and B-cell infiltration were the prognostic factors of LUAD. In addition, the 1-year negative predictive value of the POSTN expression activity for overall survival, disease-free survival, and progression-free interval was 0.902, 0.926, and 0.838, respectively. Along with decreased B-cell infiltration, the elevated expression of POSTN is an important factor of LUAD prognosis.

RPP40 is a prognostic biomarker and correlated with tumor microenvironment in uterine corpus endometrial carcinoma.

Ribonuclease P/MRP Subunit P40 (RPP40), a component of ribonuclease P and multimeric ribonuclease P complex, was reported as one of the promoting factors for the chemoresistance of acute myeloid leukemia and a recurrence predictor of early-stage triple-negative breast cancer. However, the functional role of RPP40 in uterine corpus endometrial carcinoma (UCEC) is unclear. In this study, comprehensive bioinformatic analyses were conducted to explore the predictive role of RPP40 on UCEC diagnosis and prognosis, as well as the underlying mechanism. Differential analyses of multiple databases showed that both messenger RNA (mRNA) and the protein expression of RPP40 were significantly upregulated in UCEC tumor tissues. Furthermore, the RPP40 mRNA expression level was significantly correlated with the clinicopathological characteristics of UCEC patients, including the clinical stage, primary therapy outcome, histological type, histologic grade, overall survival event, disease-specific survival event, and progression-free interval event. Receiver operating characteristic (ROC) analysis showed that RPP40 was a reliable predictor for UCEC diagnosis with an area under the curve (AUC) of 0.775, a sensitivity of 0.829, and a specificity of 0.719. Kaplan–Meier, Cox regression, and nomogram analyses showed that high RPP40 expression was an independent prognostic factor for the 1-year, 3-year, and 5-year survival of UCEC patients. In addition, the enrichment analysis of RPP40-associated differentially expressed genes and correlation analyses showed that the expression of RPP40 was correlated with the regulation of extracellular matrix and immune cell infiltration. In conclusion, the upregulation of RPP40 is significantly correlated with the poor survival and tumor microenvironment of UCEC, suggesting that RPP40 is a promising biomarker of poor prognosis and a potential target of chemotherapy or immunotherapy in UCEC.

Systematic pan-cancer analysis identifies RBM39 as an immunological and prognostic biomarker.

RNA‐binding Motif Protein39 (RBM39) is identified as a splicing factor and transcription coactivator. Despite mounting evidence that RBM39 plays a critical role in the development of specific malignancies, no systematic pan‐cancer investigation of RBM39 has been conducted. As a result, we set out to investigate RBM39’s prognostic significance and putative immunological activities in 33 different cancers. Based on TCGA and CCLE, GTEx, cBioportal and HPA, we used a series of bioinformatics approaches to explore the potential oncogenic role of RBM39, including analysis of the expression of the pan‐cancer species RBM39, the prognostic relationship between RBM39 expression and overall survival (OS), disease‐specific survival (DSS) and progression‐free interval (PFI), the relationship between RBM39 expression and clinical phenotype, analysis of the relationship between RBM39 expression and tumour mutational burden (TMB), microsatellite instability (MSI), DNA methylation and immune cell infiltration. Our results showed that RBM39 is overexpressed in most cancers. RBM39 was positively or negatively correlated with the prognosis of different tumours. RBM39 expression was associated with TMB and MSI in 9 and 12 cancer types. In addition, RBM39 expression was associated with DNA methylation in almost all tumours. There are eight tumours were screened for further study, including BRCA, COAD, HNSC, LIHC, LUSC, SKCM, STAD, UCEC. In the screed tumours, RBM39 was found to be negatively correlated with the infiltration of most immune cells. In addition, the correlation with RBM39 expression varied by immune cell subtype. Based on RBM39’s role in tumorigenesis and tumour immunity, we suggest it can serve as a surrogate prognostic marker.

Key molecules associated with thyroid carcinoma prognosis: A study based on transcriptome sequencing and GEO datasets.

BackgroundThyroid carcinoma (THCA) has a low mortality rate, but its incidence has been rising over the years. We need to pay attention to its progression and prognosis. In this study, a transcriptome sequencing analysis and bioinformatics methods were used to screen key genes associated with THCA development and analyse their clinical significance and diagnostic value.MethodsWe collected 10 pairs of THCA tissues and noncancerous tissues, these samples were used for transcriptome sequencing to identify disordered genes. The gene expression profiles were obtained from the Gene Expression Omnibus (GEO) database. Comprehensive analysis of thyroid clinicopathological data using The Cancer Genome Atlas (TCGA). R software was used to carry out background correction, normalization and log2 conversion. We used quantitative real-time PCR (qRT–PCR) and Western blot to determine differentially expressed genes (DEGs) expression in samples. We integrated the DEGs expression, clinical features and progression-free interval (PFI). The related functions and immune infiltration degree were established by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Set Enrichment Analysis (GSEA), and single-sample Gene Set Enrichment Analysis (ssGSEA). The UALCAN database was used to analyse the methylation level.ResultsWe evaluated DEGs between normal tissue and cancer. Three genes were identified: regulator of G protein signaling 8 (RGS8), diacylglycerol kinase iota (DGKI) and oculocutaneous albinism II (OCA2). The mRNA and protein expression levels of RGS8, DGKI and OCA2 in normal tissues were higher than those in THCA tissues. Better survival outcomes were associated with higher expression of RGS8 (HR=0.38, P=0.001), DGKI (HR=0.52, P=0.022), and OCA2 (HR=0.41, P=0.003). The GO analysis, KEGG analysis and GSEA proved that the coexpressed genes of RGS8, DGKI and OCA2 were related to thyroid hormone production and peripheral downstream signal transduction effects. The expression levels of RGS8, DGKI and OCA2 were linked to the infiltration of immune cells such as DC cells. The DNA methylation level of OCA2 in cancer tissues was higher than that in the normal samples.ConclusionsRGS8, DGKI and OCA2 might be promising prognostic molecular markers in patients with THCA and reveal the clinical significance of RGS8, DGKI and OCA2 in THCA.

Identification of OTUD6B as a new biomarker for prognosis and immunotherapy by pan-cancer analysis.

BackgroundOvarian-tumor (OTU) domain-containing protein 6B (OTUD6B), one of newly identified OTU deubiquitylating enzyme families, is proved to be associated with tumor progression. However, whether it plays a key role in pan-cancer still remains unknown.MethodsThe profiles of OTUD6B expression in multiple cancers were analyzed using The Cancer Genome Atlas (TCGA) database. Information of protein expression was performed based on the HPA, GeneCards, and String databases. K-M plotter and survival data analysis were used to analyze the prognostic value of OTUD6B expression, including overall survival (OS), disease-specific survival (DSS), disease-free interval (DFI), and progression-free interval (PFI). R package “clusterProfiler” was used for enrichment analysis of OTUD6B. Furthermore, we analyzed the correlation between the expression of OTUD6B, immune infiltration, and immune-related genes. Additionally, we preliminarily validated its tumorigenic effect in lung cancer cell lines.FindingsOTUD6B expression was upregulated in most cancers, such as COAD, CHOL, and LUAD, and predicted poor prognosis in most cancers in TCGA. Results showed that OTUD6B expression was positively correlated with memory CD4+ T cells, Th1 CD4+ T cells, and CD8+ T cells. In terms of the immune-related genes, OTUD6B was found to be associated with most types of genes, such as immunostimulatory genes KDR, TGFBR1, and IL-10. Moreover, for most types of tumors, the immune score was found to be negatively correlated with OTUD6B expression. In addition, lung cancer cell lines with OTUD6B knockdown significantly inhibited proliferation and invasion ability of lung cancer cells.ConclusionsThe study indicated that OTUD6B is an oncogene and may serve as a new potential biomarker in various tumors. OTUD6B may play a part in TIME, which could be applied as a new target for cancer therapy.

Identification of MAN1B1 as a Novel Marker for Bladder Cancer and Its Relationship with Immune Cell Infiltration.

Bladder cancer (BC) is a common malignant tumor of the genitourinary system, and there are not enough tumor biomarker tests that are specific, trustworthy, and noninvasive for the diagnosis and prognosis. The purpose of this study is to investigate the clinical relevance, prognostic value, and immunological signature of Mannosidase alpha class 1B member 1(MAN1B1) expressions in BC. The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases provided the raw information that was used to analyze the expression of MAN1B1 in tumor patients. Then, a statistical study was carried out to assess the correlations of MAN1B1 expression with the clinical characteristics and the prognosis of BC. The correlation between MAN1B1 expression and tumor immune infiltration was explored via single-sample gene set enrichment analysis (ssGSEA). In human cancers, MAN1B1 expressions were shown to be generally higher in tumors than in normal specimens. We confirmed that MAN1B1 expression was distinctly increased in BC specimens compared with nontumor specimens. BC specimens with advanced T stage and M stage showed a higher level of MAN1B1. Survival analysis revealed that the overall survival (OS), disease-specific survival (DSS), and progression-free interval (PFI) of patients with high MAN1B1 expressions were distinctly worse than those with low MAN1B1 expressions. Importantly, multivariate analyses only confirmed that MAN1B1 expression was an independent prognostic factor for OS of the patients with BC. Furthermore, we observed that MAN1B1 expression level was significantly correlated with abundance of multiple immune infiltrates including Th2 cells, macrophages, Th1 cells, neutrophils, T helper cells, and NK CD56 bright cells. In conjunction with all of these findings, elevated MAN1B1 expression is associated with a poor prognosis and a higher number of immune cells in BC. MAN1B1 has the potential to act as a biomarker that can evaluate both the patient's prognosis and the degree of immune infiltration in BC.

A Comprehensive Analysis of Interferon Regulatory Factor Expression: Correlation with Immune Cell Infiltration and Patient Prognosis in Endometrial Carcinoma

As a family of transcription factors, the correlations between expression pattern of nine interferon regulatory factor (IRF) family members, the immune invasion pattern, and the associated patient survival rate in endometrial carcinoma (EC) remain to be elucidated. Based on The Cancer Genome Atlas (TCGA), the expression profiles of the high and low IRF mRNA expression groups were analyzed using R (3.6.3) statistical software. Gene annotation and pathway analyses were performed using Metascape. GSEA was performed using the R package clusterProfiler (3.6.3). The single-sample gene set enrichment analysis (ssGSEA) was used to quantify the relative tumor infiltration levels of immune cell types. Immunohistochemistry data provided by HPA database was used to study the expression of the IRF proteins. Using the GEPIA dataset, the correlation between the expression of IRFs and the tumor stage of EC was analyzed. The correlations between the different IRFs were analyzed using cBioPortal. The expression of IRF2, IRF3, IRF5, IRF6, IRF7, IRF8, and IRF9 was different when comparing EC and normal endometrial samples. IRF2, IRF6, IRF7, and IRF8 were indicated to be potential diagnostic markers for EC. In combination with receiver operating characteristic analysis results, IRF2, IRF6, IRF7, and IRF8 were indicated to be potential diagnostic markers for EC. Levels of individual IRFs were associated with alternate outcomes, with the expression of IRF3 being correlated with the stage of EC and high expression of IRF4 being positively correlated with overall survival (OS); conversely, high expression of IRF5 was negatively correlated with OS. Additionally, high expression levels of both IRF2 and IRF4 were positively correlated with the disease-specific survival rate, and high expression of IRF4 was positively correlated with the progression-free interval. These data suggest a role for IRF2, IRF4, and IRF5 in the prognosis of EC. The expression of IRFs is associated with immune infiltration.

Elevated FOXA1 Expression Indicates Poor Prognosis in Liver Cancer due to Its Effects on Cell Proliferation and Metastasis.

Purpose Studying the pathogenesis of liver cancer is conducive to the exploration of effective diagnostic and prognostic biomarkers. In this study, we investigated the expression of FOXA1 and its oncogenic role in hepatocellular carcinoma (HCC). Methods Transcriptome data of HCC tissues were downloaded from The Cancer Genome Atlas (TCGA) and GEO databases and analyzed using R software. We also upregulated FOXA1 expression in HCC cells and investigated the role of FOXA1 in the proliferation and migration of HCC cells through proliferation, colony formation, wound healing, and Transwell assays. Results An analysis of the transcriptome data in TCGA database revealed found that FOXA1 is highly expressed in HCC tissues and that patients with low FOXA1 expression have a better prognosis. High FOXA1 expression was mainly associated with extracellular matrix organization, cancer, and mitosis. The results of an immunohistochemistry (IHC) assay showed that FOXA1 protein was highly expressed in HCC tissues, and patients with low FOXA1 expression showed longer disease-specific survival times and progression-free intervals. The results from quantitative reverse transcription–PCR (RT–qPCR) and Western blot experiments showed that the expression of FOXA1 in liver cancer cell lines was higher than that in immortalized human liver cell lines. Proliferation, wound healing, and Transwell experiments showed that FOXA1 enhanced the proliferation and migration abilities of liver cancer and immortalized human cell lines. Conclusion Our research suggests that FOXA1 plays an important role in promoting the recurrence and metastasis of HCC by increasing cell proliferation and metastasis.

MAFG-AS1 is a prognostic biomarker and facilitates prostate cancer progression.

Long Noncoding RNAs (LncRNAs) have recently been identified as key regulator in tumor progression. The LncRNA MAFG-AS1 has been reported to facilitate the progression of multiple cancers, however, its role in prostate cancer is still unknown. Here, we reported that MAFG-AS1 was upregulated in prostate cancer. Importantly, high expression of MAFG-AS1 indicated advanced stage prostate cancer. Univariate and Multivariate Cox regression analyses showed that high MAFG-AS1 expression was independently correlated with poor progression-free interval (PFI). According to the result of The Cancer Genome Atlas (TCGA) database and tissue microarray, high MAFG-AS1 expression indicated a poor prognosis in prostate cancer patients. In addition, gene functional enrichment analysis revealed that MAFG-AS1 may be involved in ribosome biogenesis, ribonucleoprotein complex subunit organization, ribonucleoprotein complex assembly, rRNA metabolic process, structural constituent of ribosome, and ribonucleoprotein complex binding. Furthermore, MAFG-AS1 knockdown by siRNA markedly impaired prostate cancer cell proliferation, migration, and invasion.

ELAVL1 promotes prostate cancer progression by interacting with other m6A regulators.

N6-Methyladenosine (m6A) imbalance is an important factor in the occurrence and development of prostate cancer (PCa). Many m6A regulators have been found to be significantly dysregulated in PCa. ELAVL1 is an m6A binding protein that can promote the occurrence and development of tumors in an m6A-dependent manner. In this study, we found that most m6A regulators were significantly dysregulated in PCa, and some m6A regulators were associated with the progression-free interval. Mutations and copy number variations of these m6A regulators can alter their expression. However, ELAVL1 mutations were not found in PCa. Nevertheless, ELAVL1 upregulation was closely related to PCa proliferation. High ELAVL1 expression was also related to RNA metabolism. Further experiments showed that ELAVL1 interacted with other m6A regulators and that several m6A regulatory mRNAs have m6A sites that can be recognized by ELAVL1. Additionally, protein–protein interactions occur between ELAVL1 and other m6A regulators. Finally, we found that the dysregulation of ELAVL1 expression occurred in almost all tumors, and interactions between ELAVL1 and other m6A regulators also existed in almost all tumors. In summary, ELAVL1 is an important molecule in the development of PCa, and its interactions with other m6A regulators may play important roles in PCa progression.