Uterine Corpus Endometrial Carcinoma Research Articles

Clinicopathological role of Cyclin A2 in uterine corpus endometrial carcinoma: Integration of tissue microarrays and ScRNA-Seq.

The comprehensive expression level and potential molecular role of Cyclin A2 (CCNA2) in uterine corpus endometrial carcinoma (UCEC) remains undiscovered. UCEC and normal endometrium tissues from in-house and public databases were collected for investigating protein and messenger RNA expression of CCNA2. The transcription factors of CCNA2 were identified by the Cistrome database. The prognostic significance of CCNA2 in UCEC was evaluated through univariate and multivariate Cox regression as well as Kaplan-Meier curve analysis. Single-cell RNA-sequencing (scRNA-seq) analysis was performed to explore cell types in UCEC, and the AUCell algorithm was used to investigate the activity of CCNA2 in different cell types. A total of 32 in-house UCEC and 30 normal endometrial tissues as well as 720 UCEC and 165 control samples from public databases were eligible and collected. Integrated calculation showed that the CCNA2 expression was up-regulated in the UCEC tissues (SMD = 2.43, 95% confidence interval 2.23∼2.64). E2F1 and FOXM1 were identified as transcription factors due to the presence of binding peaks on transcription site of CCNA2. CCNA2 predicted worse prognosis in UCEC. However, CCNA2 was not an independent prognostic factor in UCEC. The scRNA-seq analysis disclosed five cell types: B cells, T cells, monocytes, natural killer cells, and epithelial cells in UCEC. The expression of CCNA2 was mainly located in B cells and T cells. Moreover, CCNA2 was active in T cells and B cells using the AUCell algorithm. CCNA2 was up-regulated and mainly located in T cells and B cells in UCEC. Overexpression of CCNA2 predicted unfavorable prognosis of UCEC.

Novel targets and their functions in the prognosis of uterine corpus endometrial cancer patients.

Aberrant mRNA expression is implicated in uterine corpus endometrial carcinoma (UCEC) oncogenesis and progression. However, effective prognostic biomarkers for UCEC remain limited. We aimed to construct a reliable multi-gene risk model using gene expression profiles. Utilizing TCGA data (543 UCEC samples, 35 controls), we identified 1517 differentially acting genes. Weighted gene co-expression complex analysis (WGCCA), hub gene screening, and risk regression analysis (RRA) were employed to determine prognosis-related genes and construct the risk model. Nomograms visualized risk scores and receiver operator characteristic (ROC) curves assessed model performance. Seven novel prognosis-related hub genes (ANGPT1, ASB2, GAL, GDF7, ONECUT2, SV2B, TRPC6) were identified. The model's concordance index (C index) by multivariate Cox regression analysis was 0.79. ROC curves yielded AUCs of 0.811 (3-year) and 0.79 (5-year), demonstrating the model's efficacy in predicting UCEC survival. Our study proposes a promising seven-biomarker risk model for predicting UCEC prognosis, offering potential clinical utility.

ZNF554 Inhibits Endometrial Cancer Progression via Regulating RBM5 and Inactivating WNT/β-Catenin Signaling Pathway.

Uterine corpus endometrial carcinoma (UCEC), a kind of gynecologic malignancy, poses a significant risk to women's health. The precise mechanism underlying the development of UCEC remains elusive. Zinc finger protein 554 (ZNF554), a member of the Krüppel-associated box domain zinc finger protein superfamily, was reported to be dysregulated in various illnesses, including malignant tumors. This study aimed to examine the involvement of ZNF554 in the development of UCEC. The expression of ZNF554 in UCEC tissues and cell lines were examined by qRT-PCR and Western blot assay. Cells with stably overexpressed or knocked-down ZNF554 were established through lentivirus infection. CCK-8, wound healing, and Transwell invasion assays were employed to assess cell proliferation, migration, and invasion. Propidium iodide (PI) staining combined with fluorescence-activated cell sorting (FACS) flow cytometer was utilized to detect cell cycle distribution. qRT-PCR and Western blotting were conducted to examine relative mRNA and protein levels. Chromatin immunoprecipitation assay and luciferase reporter assay were used to explore the regulatory role of ZNF554 in RNA binding motif 5 (RBM5). The expression of ZNF554 was found to be reduced in both UCEC samples and cell lines. Decreased expression of ZNF554 was associated with higher tumor stage, decreased overall survival, and reduced disease-free survival in UCEC. ZNF554 overexpression suppressed cell proliferation, migration, and invasion, while also inducing cell cycle arrest. In contrast, a decrease in ZNF554 expression resulted in the opposite effect. Mechanistically, ZNF554 transcriptionally regulated RBM5, leading to the deactivation of the Wingless (WNT)/β-catenin signaling pathway. Moreover, the findings from rescue studies demonstrated that the inhibition of RBM5 negated the impact of ZNF554 overexpression on β-catenin and p-glycogen synthase kinase-3β (p-GSK-3β). Similarly, the deliberate activation of RBM5 reduced the increase in β-catenin and p-GSK-3β caused by the suppression of ZNF554. In vitro experiments showed that ZNF554 overexpression-induced decreases in cell proliferation and migration were counteracted by RBM5 knockdown. Additionally, when RBM5 was overexpressed, it hindered the improvements in cell proliferation and migration caused by reducing the ZNF554 levels. ZNF554 functions as a tumor suppressor in UCEC. Furthermore, ZNF554 regulates UCEC progression through the RBM5/WNT/β-catenin signaling pathway. ZNF554 shows a promise as both a prognostic biomarker and a therapeutic target for UCEC.

Structured testing of genetic association with mixed clinical outcomes.

Genetic factors play a fundamental role in disease development. Studying the genetic association with clinical outcomes is critical for understanding disease biology and devising novel treatment targets. However, the frequencies of genetic variations are often low, making it difficult to examine the variants one-by-one. Moreover, the clinical outcomes are complex, including patients' survival time and other binary or continuous outcomes such as recurrences and lymph node count, and how to effectively analyze genetic association with these outcomes remains unclear. In this article, we proposed a structured test statistic for testing genetic association with mixed types of survival, binary, and continuous outcomes. The structured testing incorporates known biological information of variants while allowing for their heterogeneous effects and is a powerful strategy for analyzing infrequent genetic factors. Simulation studies show that the proposed test statistic has correct type I error and is highly effective in detecting significant genetic variants. We applied our approach to a uterine corpus endometrial carcinoma study and identified several genetic pathways associated with the clinical outcomes.

LINC01614 is a promising diagnostic and prognostic marker in HNSC linked to the tumor microenvironment and oncogenic function.

Tumor initiation and metastasis influence tumor immune exclusion and immunosuppression. Long non-coding RNA (lncRNA) LINC01614 is associated with the prognosis and metastasis of several cancers. However, the relationship between LINC01614 and cancer immune infiltration and the biofunction of LINC01614 in head and neck squamous cell carcinoma (HNSC) remain unclear. The Genotype-Tissue Expression (GTEx) and The Cancer Genome Atlas (TCGA) datasets were used to analyze the expression difference and diagnostic value of LINC01614 in normal and tumor tissues. The correlation of pan-cancer prognosis and tumor stage of LINC01614 was analyzed based on the TCGA database. The pan-cancer association of LINC01614 expression with the tumor microenvironment (TME) including immune infiltration, expression of immune-related genes, and genomic instability parameters, was analyzed using the Spearman correlation method. The correlation between LINC01614 and tumor stemness evaluation indicators, RNA methylation-related genes, and drug resistance was also analyzed. The functional analysis of LINC01614 was performed using the clusterProfiler R package. The protein-protein interaction (PPI) network and ceRNA network of LINC01614 co-expressed genes and miRNA were constructed and visualized by STRING and Cytoscape, respectively. Finally, the cell location and influence of LINC01614 on cell proliferation and metastasis of HNSC cell lines were evaluated using FISH, CCK-8, wound-healing assay, and transwell assay. LINC01614 was found to be overexpressed in 23 cancers and showed a highly sensitive prediction value in nine cancers (AUC >0.85). LINC01614 dysregulation was associated with tumor stage in 12 cancers and significantly influenced the survival outcomes of 26 cancer types, with only Lymphoid Neoplasm Diffuse Large B-cell Lymphoma (DLBC), uterine corpus endometrial carcinoma (UCEC), and bladder urothelial carcinoma (BLCA) showing a benign influence. LINC01614 was also associated with immune cell infiltration, tumor heterogeneity, cancer stemness, RNA methylation modification, and drug resistance. The potential biological function of LINC01614 was verified in HNSC, and it was found to play important roles in proliferation, immune infiltration, immunotherapy response, and metastasis of HNSC. LINC01614 may serve as a cancer diagnosis and prognosis biomarker and an immunotherapy target for specific cancers.

Distinct roles of CD244 expression in cancer diagnosis and prognosis: A pan-cancer analysis

The abnormal expression of tumor associated genes in pan-cancer is closely related to the clinicopathological features of distinct cancer types. Thus, identifying the role of specific genes in pan-cancer is needed for developing effective anti-cancer strategies. However, the function of CD244 in pan-cancer has not been fully understood. In this study, we explored the CD244 expression profile across 33 tumor types based on The Cancer Genome Atlas project, the Gene Expression Omnibus database, and other bioinformatics tools. We found down-regulated expression levels in seven tumor types and up-regulated expression levels in two tumor types. We subsequently explored the relationship between survival rate and CD244 expression, and found the positive relationship in patients with adrenocortical carcinoma (ACC), head and neck squamous cell carcinoma (HNSC), skin cutaneous melanoma (SKCM), and uterine corpus endometrial carcinoma (UCEC). We further investigated the association between CD244 expression and tumor-infiltrating immune cells, and discovered their positive correlation in different tumors. We found that CD244 expression level was higher in normal samples than in UCEC samples, and was positively associated with CD8+ T cells infiltrating. The mutation status, promoter methylation, CD244-related molecules and signaling pathways were also employed to study the potential function of CD244 in tumor initiation and progression. Our study offers a comprehensive overview of CD244 in human tumors, revealing CD244 as a potential prognostic biomarker and immunotherapeutic target in cancers.

Abstract 1852: NCI’s Clinical Proteomic Tumor Analysis Consortium: A proteogenomic cancer analysis program

Abstract The National Cancer Institute’s Clinical Proteomic Tumor Analysis Consortium (NCI’s CPTAC) is a national effort to accelerate the understanding of cancer biology through the integration of large-scale proteome and genome analysis, or proteogenomics. The program which is composed of a Tumor Characterization Program and a Translational Research Program (proteomics.cancer.gov) aims to leverage the investments made in cancer research by understanding the molecular changes by proteogenomically characterizing cancers and accelerating the basic discovery toward clinical impact. All data and analytical tools are made broadly available to the research community through public databases to maximize utility and public benefit.CPTAC teams have characterized a plethora of treatment-naïve tumor types, including colorectal, ovarian, breast, clear cell renal cell carcinoma, uterine corpus endometrial carcinoma, lung adenocarcinoma, lung squamous cell carcinoma, brain (including adult, pediatric, and adolescent and young adult), head and neck squamous cell carcinoma, and pancreatic ductal adenocarcinoma (proteomics.cancer.gov/resources/milestones-and-publications). Ongoing projects include acute myeloid leukemia (AML), cutaneous melanoma, sarcoma, oligodendroglioma, gastric, prostate, liver, and thyroid cancers. In the PTRC Program, CPTAC is partnering with NCI-sponsored clinical trials to support clinically relevant research projects that would elucidate biological mechanisms of therapeutic response, resistance, and/or toxicity in cancers including AML, multiple myeloma, melanoma, and lung cancers. All mass spectrometry-based proteomic, genomic, and imaging data (histopathology and radiology) are made publicly available at the CPTAC Proteomic Data Commons (pdc.cancer.gov), Genomic Data Commons (gdc.cancer.gov), and the Cancer Imaging Archive (cancerimagingarchive.net)/Imaging Data Commons (imaging.datacommons.cancer.gov) respectively. CPTAC is also supporting development of new proteogenomic data analysis tools (proteomics.cancer.gov/resources/computational-tools). In addition, the CPTAC Assay Portal (assays.cancer.gov) is a public resource populated with mass spectrometry-based targeted proteomic assays developed by the consortium for quantitatively measuring proteins of interest, including those discovered through comprehensive tumor characterization. Lastly, well-characterized monoclonal antibodies targeting cancer-specific proteins and peptides are also made available at CPTAC’s Antibody Portal (antibodies.cancer.gov). Citation Format: Mehdi Mesri, Eunkyung An, Xu Zhang, Jasmin Bavarva, Ana I. Robles, Tara Hiltke, Henry Rodriguez. NCI’s Clinical Proteomic Tumor Analysis Consortium: A proteogenomic cancer analysis program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1852.

A comprehensive analysis and experimental validation of TK1 in uterine corpus endometrial carcinoma

Uterine corpus endometrial carcinoma (UCEC) is becoming a main malignant cancer that threaten to women's health. Thymidine kinase 1 (TK1) is considering to be associated with tumorigenesis and development. Nevertheless, the function of TK1 in UCEC is still unclear. Herein, we analyzed the TK1 expression level in pan-cancer and found that TK1 was upregulated in a variety of cancers including UCEC. Patients of UCEC with high expression of TK1 were related to poor outcome. TK1 was also related to clinical stage, histologic grade and lymph node metastasis. Abnormal expression of TK1 in UCEC was related to promoter methylation while gene mutation was not frequent. TK1 and its associated genes appeared to be prominent in cell cycle and DNA replication, according to GO and KEGG analysis. Analysis of immune infiltration revealed a negative correlation between TK1 and CD8 + T cells, macrophages, and dendritic cells. In vitro experiments, TK1 knockdown resulted in the inhibition of proliferation, migration, invasion and EMT in UCEC cell lines.

Comprehensive Pan-cancer Analysis of CMPK2 as Biomarker and Prognostic Indicator for Immunotherapy.

UMP-CMP kinase 2 (CMPK2) is involved in mitochondrial DNA synthesis which can be oxidized and released into the cytoplasm in innate immunity. It initiates the assembly of NLRP3 inflammasomes and mediates various pathological processes such as human immunodeficiency virus infection and systemic lupus erythematosus. However the role of CMPK2 in tumor progression and tumor immunity remains unclear. In this study we conducted a systematical analysis of CMPK2 across 33 different cancers based on datasets such as Genotype Tissue-Expression (GTEx) The Cancer Genome Atlas (TCGA) the Cancer Cell Line Encyclopedia (CCLE) and Tumor Immune Syngeneic Mouse (TISMO). Our focus encompassed the characterization of CMPK2 expression patternsclinical significance potential regulatory mechanisms and its relationship with the tumor immune profile including responsiveness to immune checkpoint inhibitor treatment. CMPK2 expression was elevated in 23 cancers and decreased in two cancers. Receiver operating characteristic curve analysis indicated that CMPK2 expression had a high diagnostic value for 16 cancers. Kaplan-Meier survival analysis showed that high CMPK2 expression was associated with Lower Overall Survival (OS)Disease- Specific Survival (DSS) and Progression-Free Interval (PFI) in Kidney Cutaneous Chromophobe (KICH) Uterine Corpus Endometrial Carcinoma (UCEC) and Uveal Melanoma (UVM) and the opposite was true in Skin Cutaneous Melanoma (SKCM). Immune microenvironment-related analysis revealed strong associations between CMPK2 expression and immune cell infiltration as well as immune checkpoint expression across various tumors. Notably in four mouse immunotherapy cohorts CMPK2 expression in treated mouse tumors was post-treatment. In five clinical immunotherapy cohorts patients with high CMPK2 expression show better responses to immunotherapy. Furthermore the methylation level of the CMPK2 gene was closely correlated to its expression and tumor prognosis. Among these cancers the clinical and immunological indications of SKCM are particularly closely related to CMPK2 expression. Our analysis preliminarily describes the complex function of CMPK2 in cancer progression and immune microenvironment highlighting its potential as a diagnostic and therapeutic target for immunotherapy.

Prognostic significance and immunological role of HPRT1 in human cancers.

Hypoxanthine phosphoribosyl transferase 1 (HPRT1), once considered a housekeeping gene, has been identified as playing an important role in several tumors. Its role in pan-cancer, however, has not been systematically studied. This study evaluates the relationship between HPRT1 and clinical parameters, survival prognosis, and tumor immunity based on multi omics data from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Drug sensitivity analysis screened 16 effective drugs against HPRT1, exploring the interactions with chemicals and genes. The significance of HPRT1 in tumor immunotherapy has also been investigated. Immunohistochemistry confirmed significant differences in the expression of HPRT1 between five tumor types (colon adenocarcinoma [COAD], head-neck squamous cell carcinoma [HNSC], lung adenocarcinoma [LUAD], thyroid carcinoma [THCA], and uterine corpus endometrial carcinoma [UCEC]) and adjacent normal tissues (P < 0.05). HPRT1 competitive endogenous RNA network was constructed in HNSC. Through cytological experiments, it was verified that HPRT1 plays a carcinogenic role in HNSC and is associated with tumor cell proliferation, migration, invasion, and apoptosis. In addition, there was a significant positive correlation between HPRT1 and programmed cell death-1 (PD-1) expression in HNSC (P < 0.05). These findings suggest that HPRT1 may be a potential biomarker for predicting and treating cancer.

The Prognostic Value and Clinical Significance of lncRNA SNHG5 Expression in Patients with Multiple Malignancies: A Bioinformatic and Meta-Analysis.

Long non-coding RNA small nucleolar RNA host gene 5 (lncRNA SNHG5) has been identified as both a promising target for treatment and a predictor of prognosis in diverse types of cancer. The objective of this study was to assess whether lncRNA SNHG5 expression can be utilized as a prognostic biomarker for human cancer. To ensure a thorough search of the literature for relevant English studies published before July 2023, several databases were searched, including PubMed, Web of Science, ProQuest, Cochrane Library, and Google Scholar. The study evaluated the impact of lncRNA SNHG5 on the overall survival (OS) of cancer by calculating the pooled hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals (CIs). To further confirm the accuracy of the findings, the study investigated the expression profile and prognostic significance of lncRNA SNHG5 through the use of GenomicScape, OncoLnc, Kaplan-Meier plotter, and GEPIA databases. In this study, 995 patients were examined across a total of fourteen original studies. The findings indicated that there was a significant relationship between heightened lncRNA SNHG5 expression and reduced OS, as evidenced by both univariate and multivariate analyses (HR = 1.89; 95% CI, 1.44-2.49; p < 0.001; HR = 3.97; 95% CI, 1.80-8.73; p < 0.001, respectively). Pooled OR analysis showed a significant association between over-expression of lncRNA SNHG5 with advanced histological grade (OR = 0.28; 95% CI, 0.11-0.71; p = 0.007), present lymph node metastasis (LNM; OR = 4.28; 95% CI, 2.47-7.43; p < 0.001), and smoking history (OR = 0.27; 95% CI, 0.15-0.49; p < 0.001). Bioinformatic databases confirmed that elevated SNHG5 expression was significantly linked to poor prognosis in cancer patients, including colorectal cancer (CRC), acute myeloid leukemia (AML), and esophageal adenocarcinoma (ESAD), and a longer OS in patients with uterine corpus endometrial carcinoma (UCEC). These results suggest that lncRNA SNHG5 may serve as an adverse prognostic biomarker in several human cancers. Further investigations are needed to better understand the underlying mechanisms that link lncRNA SNHG5 to multiple malignancies.

Development of a necroptosis-related prognostic model for uterine corpus endometrial carcinoma

Necroptosis is a recently identified caspase-independent form of cell death which plays a significant role in the onset and progression of cancer. MicroRNAs (miRNAs) are vital for the development of uterine corpus endometrial carcinoma (UCEC) because they are an important regulatory component in necroptosis. This study developed a new necroptosis-related miRNAs profile to predict the prognosis of patients with UCEC. The TCGA-UCEC cohort’s RNA sequencing data, consisting of 534 tumor samples and 33 normal samples, was downloaded. Ten differentially expressed miRNAs related to necroptosis were identified. A prediction model for necroptosis-related miRNAs was then created through COX regression and nomograms analysis. Clinical and pathological parameters were integrated to construct a nomogram and evaluate the model. Prognosis-related miRNAs were further used to predict target genes, and functional analysis was conducted to explore the potential mechanisms of these target genes. Subsequently, immune infiltration analysis was performed using transcriptome data to identify immune genes associated with prognosis, and the expression levels of target gene was validated using UCEC tissues. We identified 7 up-regulated miRNAs (hsa-miR-577, hsa-miR-7-5p, hsa-miR-210-3p, hsa-miR-210-5p, hsa-miR-200a-5p, hsa-miR-141-3p, hsa-miR-425-5p) and 3 down-regulated miRNAs (hsa-miR-7-2-3p, hsa-miR-383-5p, hsa-miR-29a-3p). The risk signature was based on univariate and multivariate COX analyses, constructed using 2 independent prognostic factors and miRNAs (hsa-miR-425-5p, hsa-miR-7-5p) associated with necroptosis. Nomograms demonstrated the prognostic value of risk level, age, FIGO stage, and histological type. Kaplan–Meier analysis revealed significant differences in overall survival (OS) outcomes associated with the expression of hsa-miR-425-5p (P < 0.001) and hsa-miR-7-5p (P = 0.015). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) investigations indicated that these miRNAs play crucial roles in tumor development, metastasis, and prognosis. Immune infiltration analysis showed decreased infiltration of CD8+ T cells, CD8+ T cells, NK cells, and M1 macrophages in normal tissues. Subsequently, a necroptosis-related immune gene significantly associated with prognosis (THRB) was identified, western blot and immunohistochemical staining confirmed the differential expression of THRB in normal endometrial tissues and tumor. Our findings demonstrate a close association between necroptosis and UCEC. The two necroptosis-related miRNAs used in this study may serve as valuable prognostic markers for UCEC patients, and are associated with immune cell infiltration. This suggests that necroptosis may be involved in the development of UCEC through its interaction with immune responses.

SPC25 Functions as a Prognostic-Related Biomarker, and Its High Expression Correlates with Tumor Immune Infiltration and UCEC Progression.

Most tumor tissues expressed spindle pole body component 25 (SPC25), one of the four subunits of the NDC80 complex, at greater levels compared to surrounding normal tissues. According to earlier researches, this subunit strongly encouraged tumor cell proliferation and tumor growth, which resulted in worse prognoses in patients with hepatocellular, breast, lung, and prostate cancer. Precisely because SPC25's role in uterine corpus endometrial carcinoma (UCEC) is understudied, we chose to concentrate on UCEC for gaining a more scientific and thorough understanding of SPC25. Along with examining SPC25's differential expression, prognostic significance, and biological function in UCEC, our research sought to clarify the underlying mechanism by which SPC25 influences the course of UCEC and patient prognosis from the viewpoints of methylation and immune infiltration. We observed differential expression of SPC25 gene in different clinicopathological features of UCEC and identified SPC25 as a hazard factor for poorer overall survival (OS), disease-specific survival (DSS), and progress free interval (PFI) in UCEC, particularly in its multiple clinical subtypes. In addition, we also discovered that SPC25 and its co-expressed genes mostly engaged in biological processes and signal transduction routes linked to cell cycle and cell division in UCEC. After investigating SPC25's methylation status, we discovered that patients with UCEC had elevated SPC25 expression and a poor prognosis due to hypomethylation of CpG sites in the SPC25 gene sequence. Finally, we investigated SPC25's potential role in immunotherapy and discovered that SPC25 might alter the major immune cell infiltration levels in the tumor microenvironment (TME) by regulating the expression of immunoregulatory molecules and chemokines, which would be beneficial for SPC25 to control the progression of UCEC. In conclusion, SPC25 was a useful predictive biomarker as well as a possible therapeutic target for UCEC.

Identification and validation of KIF23 as a hypoxia-regulated lactate metabolism-related oncogene in uterine corpus endometrial carcinoma

AimsThe “Warburg effect” has been developed from the discovery that hypoxia-inducible factor 1α (HIF-1α) could promote the conversion of pyruvate to lactate. However, no studies have linked hypoxia and lactate metabolism to uterine corpus endometrial carcinoma (UCEC). Main methodsSequencing and clinical data of patients with UCEC were extracted from The Cancer Genome Atlas (TCGA) database. Hypoxia-related lactate metabolism genes (HRLGs) were screened using Spearman's correlation analysis. A prognostic signature based on HRLGs was developed using the least absolute shrinkage and selection operator (LASSO) algorithm. A comprehensive analysis was conducted on the molecular features, immune environment, mutation patterns, and response to drugs between different risk groups. In vitro and in vivo experiments were performed to verify the function of KIF23. Key findingsA five HRLG-based prognostic signature was identified. The prognostic outcome was unfavorable for the high-risk subgroup. Observation of increased pathway activities associated with cell proliferation and DNA damage repair was noted in the high-risk subgroup. Additionally, notable correlations were observed between risk score and immune microenvironment, mutational features, and drug responsiveness. Further, we confirmed KIF23 as a novel oncogene in UCEC, whose silencing decreased proliferation and promoted apoptosis of cancer cells. KIF23 knockdown reduced tumor growth in nude mice. We demonstrated that KIF23 was upregulated under hypoxic stress in a HIF-1α dependent manner. Moreover, KIF23 regulated lactate dehydrogenase A expression. SignificanceThe developed HRLG-related signature was associated with prognosis, immune microenvironment, and drug sensitivity in UCEC. We also revealed KIF23 as a hypoxia-regulated lactate metabolism-related oncogene.

Systematic pan-cancer analyses of the potential function of the Golgi scaffold protein PAQR3

Progesterone and AdipoQ Receptor 3 (PAQR3) is a member of the AdipoQ receptor. Our previous studies have found that PAQR3 plays a role as a candidate inhibitor in cardiac adenocarcinoma, breast cancer, gastric cancer and colorectal cancer, but the systematic analysis of PAQR3 in tumors is currently lacking. The objective of this study was to investigate the prognostic and therapeutic value of PAQR3 in 31 tumors. Through the analysis of TCGA, UALCAN, GEO, GEPIA2, TIMER, Kaplan–Meier plotter, TISIDB and other databases, it was found that the expression level of PAQR3 changed significantly in different tumor types, and the expression level of Neuroblastoma was very high. And the level of Prostate adenocarcinoma is low. In addition, the expression level of PAQR3 in Cholangiocarcinoma, Esophageal carcinoma, Head and neck squamous carcinoma, Liver Hepatocellular Carcinoma, Lung Adenocarcinoma and Lung squamous cell carcinoma was significantly higher than that in normal tissues. However, the expression level of PAQR3 in Breast Cancer, Kidney Renal Clear Cell Carcinoma, Kidney renal papillary cell carcinoma, Prostate Adenocarcinoma, Rectum Adenocarcinoma, Thyroid Cancer and Uterine Corpus Endometrial Carcinoma was lower than that in normal tissues. Subsequently, we explored the value of PAQR3 as a prognostic indicator of cancer. In Acute Myeloid Leukemia, Lower-grade Glioma and Glioblastoma, Pediatric Low-grade Gliomas, Kidney Chromophobe, and Thyroid Cancer, PAQR3 expression was positively correlated with OS and DSS, while in Rectum Adenocarcinoma, PAQR3 expression was negatively correlated with OS. PAQR3 high expression group Lower-grade Glioma and Glioblastoma, Pediatric Low-grade Gliomas, Uveal Melanoma, Kidney Chromophobe and DFI were positively correlated. PAQR3 can be used as a risk factor for the prognosis of multiple tumors. Then, we discussed the correlation between PAQR3 and immunology, and found that PAQR3 has a wide range of mutations in various tumor types, the most common mutation type is missense mutation, and common mutation types also include amplification, depth deletion, splicing, truncation and structural variation. Among the tumor samples with PAQR3 alterations, mutation occurred in all tumor samples except prostate adenocarcinoma and adrenal cortical carcinoma, head and neck squamous cell carcinoma, brain low-grade glioma, and kidney clear cell carcinoma, while esophageal adenocarcinoma had the highest total alteration frequency. PAQR3 was strongly associated with CNV in 18 tumors, particularly in Ovarian cancer, Lung squamous cell carcinoma, and Adenoid cystic carcinoma. On the other hand, PAQR3 has a higher SNV frequency in Uterine Corpus Endometrial Carcinoma, Skin Cutaneous Melanoma and Lung Adenocarcinoma, among which Uterine Corpus Endometrial Carcinoma has the highest SNV frequency. These results showed that PAQR3 expression levels were significantly correlated with tumor mutation load, microsatellite instability, neoantigens, and purity. In summary, PAQR3 can affect the tumor microenvironment and has potential for chemotherapy. Finally, we investigated the role of PAQR3 in tumor resistance and found that the expression of PAQR3 affects the efficacy of multiple chemotherapy drugs. Based on these studies, we found that PAQR3 plays an important role in cancer and has potential in tumor diagnosis and prognosis.

Machine learning combined with single-cell analysis reveals predictive capacity and immunotherapy response of T cell exhaustion-associated lncRNAs in uterine corpus endometrial carcinoma

BackgroundThe exhaustion of T-cells is a primary factor contributing to immune dysfunction in cancer. Long non-coding RNAs (lncRNAs) play a significant role in the advancement, survival, and treatment of Uterine Corpus Endometrial Carcinoma (UCEC). Nevertheless, there has been no investigation into the involvement of lncRNAs associated with T-cell exhaustion (TEXLs) in UCEC. The goal of this work is to establish predictive models for TEXLs in UCEC and study their related immune features. MethodsUsing transcriptome and single-cell sequencing data from The Cancer Genome Atlas and Gene Expression Omnibus databases, we employed co-expression analysis and univariate Cox regression to identify prognostic-associated TEXLs (pTEXLs). The prognostic model was developed using the Least Absolute Contraction and Selection Operator. The immunotherapy characteristics of the prognostic model risk score were studied. Then molecular subgroups were identified through non-negative Matrix Factorization based on pTEXLs. The identification of co-expressed genes was done using a weighted correlation network analysis. Subsequently, a diagnostic model for UCEC was created. In-depth investigations, both in vitro and in vivo, were carried out to elucidate the molecular mechanism of the key gene within the diagnostic model. ResultsReceiver operating characteristic curve, calibration curve, and decision curve analysis proved the validity of the predictive models established according to pTEXLs. The subgroup with lower risk scores in the prognostic model has better responses to blocking immune checkpoint therapy. Single-cell analysis suggests that the expression level of MIEN1 is relatively high in immune cells among diagnostic genes. Furthermore, the targeted suppression of MIEN1 via sh-MIEN1 diminishes the proliferative, migratory, and invasive capacities of UCEC cells, potentially associated with CD8+ T cell exhaustion. ConclusionsThe association between TEXLs and UCEC was methodically elucidated by our investigation. A stable pTEXLs risk prediction model and a diagnosis model for UCEC were also established.

Depleted-MLH1 Expression Predicts Prognosis and Immunotherapeutic Efficacy in Uterine Corpus Endometrial Cancer: An In Silico Approach

Uterine corpus endometrial carcinoma (UCEC) poses significant clinical challenges due to its high incidence and poor prognosis, exacerbated by the lack of effective screening methods. The standard treatment for UCEC typically involves surgical intervention, with radiation and chemotherapy as potential adjuvant therapies. In recent years, immunotherapy has emerged as a promising avenue for the advanced treatment of UCEC. This study employs a multi-omics approach, analyzing RNA-sequencing data and clinical information from The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), and GeneMANIA databases to investigate the prognostic value of MutL Homolog 1 (MLH1) gene expression in UCEC. The dysregulation of MLH1 in UCEC is linked to adverse prognostic outcomes and suppressed immune cell infiltration. Gene Set Enrichment Analysis (GSEA) data reveal MLH1’s involvement in immune-related processes, while its expression correlates with tumor mutational burden (TMB) and microsatellite instability (MSI). Lower MLH1 expression is associated with poorer prognosis, reduced responsiveness to Programmed cell death protein 1 (PD-1)/Programmed death-ligand 1 (PD-L1) inhibitors, and heightened sensitivity to anti-cancer agents. This comprehensive analysis establishes MLH1 as a potential biomarker for predicting prognosis, immunotherapy response, and drug sensitivity in UCEC, offering crucial insights for the clinical management of patients.

Systematic pan-cancer analysis of RNF186 with potential implications in progression and prognosis in human cancer

AimsCancer remains a significant global public health issue. There is growing proof that Ring Finger Protein 186 (RNF186) may play a function in pan-cancer, however, this has not yet been thoroughly determined. This study aims to analyze RNF186 with potential implications in progression and prognosis in human cancer. Materials and methodsA comprehensive bioinformatics approaches combined with experimental verification were used across 33 types of cancers in this study to conduct a pan-cancer investigation of RNF186 from the perspectives of gene expression, prognosis, genomic alterations, immunological markers, gene set, and function. Key findingsRNF186 is a valuable prognostic biomarker in several cancer types, especially breast invasive carcinoma (BRCA) and uterine corpus endometrial carcinoma (UCEC). The levels of RNF186 promoter methylation and genetic alterations may be responsible for some cancers' abnormal expression. Furthermore, RNF186 expression was determined to be associated with immune checkpoint genes. Analysis of RNF186-related genes revealed that proteasome and PI3K-AKT signaling pathway were primarily involved in the cellular function of RNF186. Additionally, our research first confirmed that RNF186 may function as an oncogene and contribute to cancer proliferation, migration and invasion in UCEC. In contrast, RNF186 may play an inhibitory role in BRCA progression. This function depends on the ligase activity of RNF186. SignificanceThis study suggests that RNF186 is a novel critical target for tumor progression in BRCA and UCEC. It reveals that RNF186 may be associated with tumor immunotherapy, which may provide an effective predictive evaluation of the prognosis of immunotherapy.

CXC chemokines: Potential biomarker and immunotherapeutic target for uterine corpus endometrial carcinoma.

Uterine corpus endometrial carcinoma (UCEC) is one of the most common type of gynecological malignancies. Multiple lines of evidence indicated that CXC chemokines exerted an anti-tumor immunological role in the tumor microenvironment which were critical regulators of cancer immunity. However, the relevance of CXC chemokines in the evaluation of prognosis and immune infiltration of UCEC remains to be explored. This study utilized various online databases, including TCGA, UALCAN, Kaplan-Meier Plotter, cBioPortal, TIMER2.0, TISIDB, and MethSurv to perform the analysis. Gene expression data from the TCGA-UCEC dataset indicated decreased expression of CXCL2/12 and increased expression of CXCL14/17. CXCL2/12 expression was negatively whereas CXCL14/17 expression was positively correlated with clinicopathological features of UCEC patients, including cancer stage, patients' age, weight and menopause status. Patients with higher CXCL12/14 expression corresponded with better clinical outcomes, which were not influenced by the genetic alterations. The differential expression of CXCL2/12/14/17 was not only significantly correlated with immune infiltration levels, but also the abundance of immune checkpoint inhibitors. Heatmaps of DNA methylation of CXCL2/12/14/17 were investigated, and 4 CpGs of CXCL2, 16 CpGs of CXCL12, 3 CpGs of CXCL14/17 were identified where altered methylation affected the prognosis of UCEC patients. These findings provided novel insights into the immunologic features of UCEC and might pave the way toward the prognostic evaluation and immunotherapy selection based on CXCL2/12/14/17 expression status.

Race, Prevalence of POLE and POLD1 Alterations, and Survival Among Patients With Endometrial Cancer.

Black patients with endometrial cancer (EC) in the United States have higher mortality than patients of other races with EC. The prevalence of POLE and POLD1 pathogenic alterations in patients of different races with EC are not well studied. To explore the prevalence of and outcomes associated with POLE and POLD1 alterations in differential racial groups. This retrospective cohort study incorporated the largest available data set of patients with EC, including American Association for Cancer Research Project GENIE (Genomics Evidence Neoplasia Information Exchange; 5087 participants), Memorial Sloan Kettering-Metastatic Events and Tropisms (1315 participants), and the Cancer Genome Atlas Uterine Corpus Endometrial Carcinoma (517 participants), collected from 2015 to 2023, 2013 to 2021, and 2006 to 2012, respectively. The prevalence of and outcomes associated with POLE or POLD1 alterations in EC were evaluated across self-reported racial groups. Patients of different racial groups with EC and with or without POLE or POLD1 alterations. The main outcome was overall survival. Data on demographic characteristics, POLE and POLD1 alteration status, histologic subtype, tumor mutation burden, fraction of genome altered, and microsatellite instability score were collected. A total of 6919 EC cases were studied, of whom 444 (6.4%), 694 (10.0%), and 4869 (70.4%) patients were self-described as Asian, Black, and White, respectively. Within these large data sets, Black patients with EC exhibited a lower weighted average prevalence of pathogenic POLE alterations (0.5% [3 of 590 cases]) compared with Asian (6.1% [26 of 424]) or White (4.6% [204 of 4520]) patients. By contrast, the prevalence of POLD1 pathogenic alterations was 5.0% (21 cases), 3.2% (19 cases), and 5.6% (255 cases) in Asian, Black, and White patients with EC, respectively. Patients with POLD1 alterations had better outcomes regardless of race, histology, and TP53 alteration status. For a total of 241 clinically annotated Black patients with EC, a composite biomarker panel of either POLD1 or POLE alterations identified 7.1% (17 patients) with positive outcomes (1 event at 70 months follow up) in the small sample of available patients. In this retrospective clinicopathological study of patients of different racial groups with EC, a composite biomarker panel of either POLD1 or POLE alteration could potentially guide treatment de-escalation, which is especially relevant for Black patients.