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Transcription factor 3 (TCF3), a pivotal member of the TCF/LEF family, plays a critical role in tumorigenesis. Nonetheless, its impact on the tumor microenvironment (TME) and cancer phenotypes remains elusive. We perform an exhaustive analysis of TCF3 expression, DNA variation profiles, prognostic implications, and associations with the TME and immunological aspects. This study is based on a large-scale pan-cancer cohort, encompassing over 17,000 cancer patients from multiple independent datasets, validated by in vitro assays. Our results show that TCF3/4/7 exhibits differential expression patterns between normal and tumor tissues across pan-cancer analyses. Mutational analysis of TCF3 across diverse cancer types reveals the highest alteration rates in biliary tract cancer. Additionally, mutations and single nucleotide variants in TCF3/4/7 are found to exert varied effects on patient prognosis. Importantly, TCF3 emerges as a robust predictor of survival across all cancer cohorts and among patients receiving immune checkpoint inhibitors. Elevated TCF3 expression is correlated with more aggressive cancer subtypes, as validated by immunohistochemistry and diverse cohort data. Furthermore, TCF3 expression is positively correlated with intratumoral heterogeneity and angiogenesis. In vitro investigations demonstrate that TCF3 is involved in epithelial-mesenchymal transition, migration, invasion, and angiogenesis. These effects are likely mediated through the interaction of TCF3 with the NF-κB/MMP2 pathway, which is modulated by IL-17A in human uveal melanoma MUM2B cells. This study elucidates, for the first time, the significant associations of TCF3 with DNA variation profiles, prognostic outcomes, and the TME in multiple cancer contexts. TCF3 holds promise as a molecular marker for diagnosis and as a potential target for novel therapeutic strategies, particularly in uveal melanoma.

OBJECTIVE: Recent studies have increasingly linked Ephrin receptor B2 (EPHB2) to cancer progression. However, comprehensive investigations into the immunological roles and prognostic significance of EPHB2 across various cancers remain lacking.
METHODS: We employed various databases and bioinformatics tools to investigate the impact of EPHB2 on prognosis, immune infiltration, genome instability, and response to immunotherapy. Validation of the correlation between EPHB2 expression and M2 macrophages included analyses using bulk and single-cell transcriptomic datasets, spatial transcriptomics, and multi-fluorescence staining. Moreover, we performed cMap web tool to screen for EPHB2-targeted compounds and assessed their potential through molecular docking and dynamics simulations. Additionally, in vitro validation using lung adenocarcinoma (LUAD) cell lines was conducted to confirm the bioinformatics predictions about EPHB2.
RESULTS: EPHB2 dysregulation was observed across multiple cancer types, where it demonstrated significant diagnostic and prognostic value. Gene Set Enrichment Analysis (GSEA) indicated that EPHB2 is involved in enhancing cellular proliferation, invasiveness of cancer cells, and modulation of the anti-cancer immune response. Furthermore, it is emerged as a pan-cancer marker for M2 macrophage infiltration, supported by integrated analyses of transcriptomics and multiple fluorescence staining. In LUAD cells, knockdown of EPHB2 expression led to a decrease in both cell proliferation and migratory activity.
CONCLUSIONS: EPHB2 expression may serve as a pivotal indicator of M2 macrophage infiltration, offering vital insights into tumor dynamics and progression across various cancers, including lung adenocarcinoma, highlighting its significant prognostic and therapeutic potential for further exploration.

BACKGROUND: Cyclin D1 (CCND1) plays a crucial role in cell cycle regulation and has been implicated in various cancers. As is well known, cancer is caused by the accumulation of detrimental variations in the genome. In this study, we shed light on the role of CCND1 in the diagnosis and progression of cancer and aimed to provide a comprehensive analysis of CCND1 across multiple cancer types, focusing on its expression, clinical correlations, DNA methylation status, prognostic implications, genetic alterations, and immune infiltration.
METHODS: Gene expression analysis of CCND1 was conducted across 33 cancer types using the TIMER, GEPIA, and UALCAN databases. Clinical parameters were investigated to assess their correlations with CCND1 expression. Methylation analysis was performed using the UALCAN and GSCA databases to investigate the relationship between CCND1 promoter methylation and gene expression and their association with survival. Immune infiltration and survival analyses were performed to explore the prognostic implications of CCND1 expression in various cancers. Statistical tests, such as the Cox proportional hazards model and the Kaplan-Meier analysis, were used to assess survival outcomes. Additionally, genetic alteration analysis was performed using the cBioPortal database to examine the prevalence and types of CCND1 alterations across different cancer types.
RESULTS: CCND1 expression was significantly elevated in 13 cancers compared to normal tissues, with distinct patterns observed across different cancer types. It is highly expressed in BLCA, CHOL, COAD, ESCA, GBM, HNSC, KIRC, PAAD, RRAD, READ, STAD, THCA, and UCEC. The investigation of clinical parameters revealed associations between CCND1 expression and factors such as age, gender, race, and cancer stage. The methylation analysis highlighted hypomethylation of CCND1 across the 13 selected cancer types. The survival analysis identified both favorable and unfavorable prognostic implications of CCND1 expression in different cancers and revealed that a high expression of CCND1 was associated with a poor prognosis in HNSC and PAAD, while a high expression of CCND1 was associated with a good prognosis in KIRC, STAD, THCA, and UCEC. In the immune infiltration analysis of various cancers, many statistically significant correlations were observed between the immune cell types and tumor purity. For example, in BLCA, neutrophils and dendritic cells showed statistically significant positive correlations and a negative correlation with macrophages. While in CHOL patients, none of the immune cell types showed a significant correlation. Similar statistical significance was observed in other cancer types, such as COAD, HNSC, GBM, KIRC, PAAD, PRAD, READ, and STAD, with different immune cell types. The genetic alteration analysis revealed that amplification was the predominant genetic alteration type in CCND1, with specific patterns observed in different cancer types.
CONCLUSIONS: The findings of this study provide valuable insights into the role of CCND1 in cancer diagnosis and progression, and its potential for targeted therapies. CCND1 could be used as a potential diagnostic biomarker for the COAD, ESCA, KIRC, READ, STAD, and THCA stages. Furthermore, CCND1 could be used as a potential prognostic biomarker for HNSC, KIRC, and PAAD. Also, the correlation between CCND1 methylation and expression could be used as a potential diagnostic and prognostic biomarker for ESCA, HNSC, and STAD.

UNASSIGNED: Recently, the role of inorganic pyrophosphatase 2 (PPA2) has been remaining merely superficial in many tumors. Hence, the aim was to analyze the potential functions of PPA2 in pan-cancer, focusing on its role in breast cancer.
UNASSIGNED: A systematic pan-cancer analysis conducted primarily utilizing various open databases such as TCGA and GTEx. We explored the clinical value of PPA2 as well as various biological functions, including expression levels and subcellular localization, multi-dimensional immune-correlation analysis, co-expression networks, and gene heterogeneity. In addition, we not only verified the function of PPA2 through cell experiments but also analyzed PPA2 at the single-cell level and its drug sensitivity.
UNASSIGNED: PPA2 is abnormally expressed in various tumors, and it is mainly distributed in mitochondria. Furthermore, the indicators (OS, DSS, DFI, and PFI) of analysis hint that PPA2 exhibits significant prognostic value. At the same time, the genomic heterogeneity (including TMB, MSI, MATH, and NEO) of PPA2 in pan-cancer was analyzed. Across multiple tumors, the results showed a close correlation between PPA2 expression levels and different immune signatures (such as immune cell infiltration). All of these indicate that PPA2 could potentially be applied in the guidance of immunotherapy. We also have demonstrated that PPA2 promoted the process of breast cancer. Finally, some potential therapeutic agents (such as Fulvestrant) targeting the abnormal expression of PPA2 are revealed.
UNASSIGNED: In conclusion, the results demonstrated the great value of PPA2 in pan-cancer research, as well as its potential as a therapeutic target for breast tumors.

The deletion of geranylgeranyl diphosphate synthase 1 (GGPS1) has been reported to inhibit the proliferation of multiple cells. Although emerging evidence has demonstrated a correlation between GGPS1 and cancer, no pan-cancer analysis has been conducted to date. This study explored the potential tumorigenesis of GGPS1 using data from the cancer genome atlas human clinical database. GGPS1 expression was considerably upregulated at both the RNA and protein levels in several cancer types, especially in breast carcinoma (BRCA), (liver) hepatocellular carcinoma (LIHC/HCC) and lung adenocarcinoma (LUAD). Amplification is the most common form of genetic alteration observed in invasive BRCA, ovarian epithelial tumor and HCC. Additionally, elevated GGPS1 expression was markedly related to poor patient prognosis and overall survival in several cancer types including LIHC. GGPS1 expression was also linked to cancer-associated fibroblasts (CAFs) infiltration in several cancer types, such as BRCA and LUAD. Moreover, GGPPS-interacting proteins and GGPS1-correlated genes in cancers were functionally enriched in terpenoid backbone biosynthesis, steroid biosynthesis, and metabolic pathways. These results indicate that GGPS1 may play a role in promoting the tumorigenesis and tumor development, particularly in BRCA and LUAD, and may play a role in steroid biosynthesis and metabolic pathways.

Protein disulfide isomerase A3 (PDIA3) is an endoplasmic reticulum (ER) protein. It has different functions including glycoprotein folding in the ER. The unfavorable prognosis of cancer patients was related to the abnormal PDIA3 expression level. However, it is unclear how PDIA3 correlates with the malignant characteristics of different tumors and its impact on tumor immunity. Pan-cancer data were downloaded from several databases for large-scale bioinformatics analysis. The immunological functions of PDIA3 were systematically explored at the single-cell sequencing level, including cell communication, cell metabolism, cell evolution and epigenetic modification. We performed immunofluorescence staining to visualize PDIA3 expression and infiltration of macrophages in pan-cancer samples. Further, we performed a loss-of-function assay of PDIA3 in vitro. The CCK8 assay, clone formation assay, and transwell assay were performed. M2 macrophages were co-cultured with different cell lines before the transwell assay was performed. The immunofluorescence staining of pan-cancer samples presented a higher expression of PDIA3 than those of the paired normal tissues. According to single-cell sequencing analysis, expression of PDIA3 was closely associated with cell communication, cell metabolism, cell evolution and epigenetic modification. The knockdown of PDIA3 in tumor cells inhibited cell proliferation and invasion, and restrained cocultured M2 macrophage migration. Furthermore, PDIA3 displayed predictive value in immunotherapy response in human cancer cohorts, indicating a potential therapeutic target. Our study showed that PDIA3 was associated with tumor malignant characteristics and could mediate the migration of M2 macrophages in various tumor types. PDIA3 could be a promising target to achieve tumor control and improve the immune response on a pan-cancer scale.

Pyrroline-5-carboxylate reductase (PYCR) is pivotal in converting pyrroline-5-carboxylate (P5C) to proline, the final step in proline synthesis. Three isoforms, PYCR1, PYCR2, and PYCR3, existed and played significant regulatory roles in tumor initiation and progression. In this study, we first assessed the molecular and immune characteristics of PYCRs by a pan-cancer analysis, especially focusing on their prognostic relevance. Then, a kidney renal clear cell carcinoma (KIRC)-specific prognostic model was established, incorporating pathomics features to enhance predictive capabilities. The biological functions and regulatory mechanisms of PYCR1 and PYCR2 were investigated by in vitro experiments in renal cancer cells. The PYCRs\' expressions were elevated in diverse tumors, correlating with unfavorable clinical outcomes. PYCRs were enriched in cancer signaling pathways, significantly correlating with immune cell infiltration, tumor mutation burden (TMB), and microsatellite instability (MSI). In KIRC, a prognostic model based on PYCR1 and PYCR2 was independently validated statistically. Leveraging features from H&E-stained images, a pathomics feature model reliably predicted patient prognosis. In vitro experiments demonstrated that PYCR1 and PYCR2 enhanced the proliferation and migration of renal carcinoma cells by activating the mTOR pathway, at least in part. This study underscores PYCRs\' pivotal role in various tumors, positioning them as potential prognostic biomarkers and therapeutic targets, particularly in malignancies like KIRC. The findings emphasize the need for a broader exploration of PYCRs\' implications in pan-cancer contexts.

Drugs that target immune checkpoint have become the most popular weapon in cancer immunotherapy, yet only have practical benefits for a small percentage of patients. Tumor cells constantly interact with their microenvironment, which is made up of a variety of immune cells as well as endothelial cells and fibroblasts. Immune checkpoint expression and blocked signaling of immune cells in the tumor microenvironment (TME) are key to tumor progression. In this study, we perform deliberation convolution on the TCGA database for human lung, breast, and colorectal cancer to infer crosstalk between immune checkpoint receptors (ICRs) and ligands (ICLs) in TME of pan-carcinogenic solid tumor types, validated by flow cytometry. Analysis of immune checkpoints showed that there was little variation between different tumor types. It showed that CD160, LAG3, TIGIT were found to be highly expressed in CD8+ T cells instead of CD4+ T cells, PD-L1, PD-L2, CD86, LGALS9, TNFRSF14, LILRB4 and other ligands were highly expressed on macrophages, FVR, NECTIN2, FGL1 were highly expressed on Epithelial cells, CD200 was highly expressed in Endothelial cells, and CD80 was highly expressed in CD8 High expression on T cells. Overall, our study provides a new resource for the expression of immune checkpoints in TME on various types of cells. Significance: This study provides immune checkpoint expression of immune cells of multiple cancer types to infer immune mechanisms in the tumor microenvironment and provide ideas for the development of new immune checkpoint-blocking drugs.

UNASSIGNED: This study aimed to systematically dissect the role of Scinderin (SCIN) in tumorigenesis.
UNASSIGNED: Bioinformatics techniques were employed based on cancer data from TCGA, ENCORI, HPA, GEPIA2, UALCAN, Kaplan-Meier plotter, TIMER, TISIDB, cBioPortal, HCCDB, GeneMANIA and LinkedOmics database. Experiments in vitro and in vivo were conducted to dissect the role of SCIN in liver hepatocellular carcinoma (LIHC).
UNASSIGNED: Significantly differential expression of SCIN was found in nine types of cancers, including LIHC. Through pan-cancer analysis, the correlations between SCIN expression with prognosis and immune cell infiltration were proven, especially in LIHC, ovarian serous cystadenocarcinoma and lung adenocarcinoma. The highest frequency of alteration in SCIN (6.81%) was seen in patients with uterine corpus endometrial carcinoma, in which \"mutation\" was the predominant type, with a frequency of about 5.29%; meanwhile, S673F and S381Y were the two most frequent mutation sites. Furthermore, the abnormal expression of SCIN exhibited a strong relationship with immune cell subtypes, immune checkpoint genes, tumor mutation burden, microsatellite instability, neoantigen, molecular subtypes, mismatch repair signatures and DNA methyl-transferase in different cancer types. Through comparative analysis, we discovered that SCIN was dramatically up-regulated in LIHC, and associated with poor survival. Experiments in vitro and in vivo suggested the knockdown of SCIN could suppress tumor cell proliferation and improve the survival rate partly in animal models.
UNASSIGNED: This study reveals SCIN may be a promising biomarker for prognosis and treatment in certain cancers, especially in LIHC.