The comprehensive landscape of prognosis, immunity, and function of the GLI family by pan-cancer and single-cell analysis.

The Hedgehog (Hh) signaling pathway has been implicated in the pathogenesis of various cancers. However, the roles of the downstream GLI family (GLI1, GLI2, and GLI3) in tumorigenesis remain elusive. This study aimed to unravel the genetic alterations of GLI1/2/3 in cancer and their association with the immune microenvironment and related signaling pathways. Firstly, we evaluated the expression profiles of GLI1/2/3 in different cancer types, analyzed their prognostic and predictive values, and assessed their correlation with tumor-infiltrating immune cells. Secondly, we explored the relationships between GLI1/2/3 and genetic mutations, epigenetic modifications, and clinically relevant drugs. Finally, we performed enrichment analysis to decipher the underlying mechanisms of GLI1/2/3 in cancer initiation and progression. Our results revealed that the expression levels of GLI1/2/3 were positively correlated in most cancer tissues, suggesting a cooperative role of these factors in tumorigenesis. We also identified tissue-specific expression patterns of GLI1/2/3, which may reflect the distinct functions of these factors in different cell types. Furthermore, GLI1/2/3 expression displayed significant associations with poor prognosis in several cancers, indicating their potential as prognostic biomarkers and therapeutic targets. Importantly, we found that GLI1/2/3 modulated the immune microenvironment by regulating the recruitment, activation, and polarization of cancer-associated fibroblasts, endothelial cells, and macrophages. Additionally, functional enrichment analyses indicated that GLI1/2/3 are involved in the regulation of epithelial-mesenchymal transition (EMT). Together, our findings shed new light on the roles of GLI1/2/3 in tumorigenesis and provide a potential basis for the development of novel therapeutic strategies targeting GLI-mediated signaling pathways in cancer.

Systematic analysis of the prognostic value and immunological function of LTBR in human cancer.

Lymphotoxin beta receptor (LTBR) is a positive T cell proliferation regulator gene. It is closely associated with the tumor immune microenvironment. However, its role in cancer and immunotherapy is unclear. Firstly, the expression level and prognostic value of LTBR were analyzed. Secondly, the expression of LTBR in clinical stages, immune subtypes, and molecular subtypes was analyzed. The correlation between LTBR and immune regulatory genes, immune checkpoint genes, and RNA modification genes was then analyzed. Correlations between LTBR and immune cells, scores, cancer-related functional status, tumor stemness index, mismatch repair (MMR) genes, and DNA methyltransferase were also analyzed. In addition, we analyzed the role of LTBR in DNA methylation, mutational status, tumor mutation burden (TMB), and microsatellite instability (MSI). Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA) were used to explore the role of LTBR in pan-cancer. Finally, the drugs associated with LTBR were analyzed. The expression of LTBR was confirmed using quantitative real-time PCR and Western blot. LTBR is significantly overexpressed in most cancers and is associated with low patient survival. In addition, LTBR expression was strongly correlated with immune cells, score, cancer-related functional status, tumor stemness index, MMR genes, DNA methyltransferase, DNA methylation, mutational status, TMB, and MSI. Enrichment analysis revealed that LTBR was associated with apoptosis, necroptosis, and immune-related pathways. Finally, multiple drugs targeting LTBR were identified. LTBR is overexpressed in several tumors and is associated with a poor prognosis. It is related to immune-related genes and immune cell infiltration.

Systematic pan-cancer analysis of the potential tumor diagnosis and prognosis biomarker P4HA3.

Purpose: Prolyl 4-hydroxylase subunit alpha 3 (P4HA3) is implicated in several cancers' development. However, P4HA3 has not been reported in other cancers, and the exact mechanism of action is currently unknown. Materials and methods: First, the expression profile of P4HA3 was analyzed using a combination of the University of California Santa Cruz (UCSC) database, Cancer Cell Line Encyclopedia (CCLE) database, and Genotype-Tissue Expression (GTEx) database. UniCox and Kaplan-Meier were used to analyze the predictive value of P4HA3. The expression of P4HA3 was analyzed in clinical staging, immune subtypes, and Molecular subtypes. Secondly, the correlation of P4HA3 with immunomodulatory genes, immune checkpoint genes, RNA modification genes, immune cell infiltration, cancer-related functional status, tumor stemness index, DNA mismatch repair (MMR) genes and DNA Methyltransferase was examined. The role of P4HA3 in DNA methylation, copy number variation (CNV), mutational status, tumor mutational burden (TMB), and microsatellite instability (MSI) was also analyzed. In addition, gene set enrichment analysis (GSEA) was used to explore the potential functional mechanisms of P4HA3 in pan-cancer. Finally, P4HA3-related drugs were searched in CellMiner, Genomics of Drug Sensitivity in Cancer (GDSC), and Cancer Therapeutics Response Portal (CTRP) databases. Results: P4HA3 is significantly overexpressed in most cancers and is associated with poor prognosis. P4HA3 is strongly associated with clinical cancer stage, immune subtypes, molecular subtypes, immune regulatory genes, immune checkpoint genes, RNA modifier genes, immune cell infiltration, cancer-related functional status, tumor stemness index, MMR Gene, DNA Methyltransferase, DNA methylation, CNV, mutational status, TMB, and MSI are closely related. Available enrichment analysis revealed that P4HA3 is associated with the epithelial-mesenchymal transition and immune-related pathways. There are currently 20 drugs associated with P4HA3. Conclusion: In human pan-cancer, P4HA3 is associated with poor patient prognosis and multiple immune cells and may be a novel immunotherapeutic target. It may act on tumor progression through the epithelial-mesenchymal transition (EMT) pathway.

Analyzing the prognostic value of DKK1 expression in human cancers based on bioinformatics.

BACKGROUND: The Dickkopf1 (DKK1) gene encodes a protein that belongs to the Dickkopf family. The protein can inhibit the Wnt signaling pathway which plays a key role in the carcinogenesis and progression of various types of cancers. Based on this, we hypothesized that the differential expression of DKK1 may figure significantly in cancers by regulating Wnt signaling pathway transduction. In this study, we conducted bioinformatics analysis to evaluate the prognostic and therapeutic value of DKK1 expression level in human cancers. METHODS: The expression level was analyzed by using the Oncomine database and Gene Expression Profiling Interactive Analysis tool. The analysis of prognosis was conducted by using the UALCAN, Gene Expression Profiling Interactive Analysis (GEPIA), and DriverDBv3 databases. We also investigated using DKK1 promoter methylation to define cancer types through the UALCAN database. Meanwhile, the related functional networks of DKK1 were analyzed by using the GeneMANIA interactive tool and Cytoscape software. Furthermore, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis was conducted using the Metascape online website, and we used the cBioPotartal database to explored DKK1 expression, aberrant information, and the co-expression genes in the subgroups of lung cancer. Finally, we performed the overall survival (OS) meta-analysis of the DKK1 expression in lung squamous cell carcinoma (LUSC) via the Lung Cancer Explorer (LCE). RESULTS: DKK1 was differentially expressed in different types of human cancers. DKK1 was overexpressed in human cancers including head and neck squamous cell carcinoma (HNSC), LUSC, and pancreatic adenocarcinoma (PAAD). Overexpression of DKK1 indicated adverse OS in bladder urothelial carcinoma (BLCA), HNSC, and PADD, but no difference in OS was found between the LUSC and healthy groups. The high expression of DKK1 was also associated with shorter disease-free survival (DFS) in HNSC, LUSC, and PAAD. Gene regulation network analysis indicated that DKK1 was mainly involved in Wnt signaling pathways and several other signaling pathways. CONCLUSIONS: Our findings showed that DKK1 is significantly expressed in various cancers and could be a biomarker for targeted therapy and a predictor for prognosis of these specific cancers. The bioinformatics analysis revealed a significant overexpression of DKK1 in HNSC, LUSC, and PAAD, with DKK1 overexpression being associated with adverse outcome in these patients, but how DKK1 expression levels relate to hematological malignancies and prognosis is still unclear. These new insights into the function of DKK1 may provide a basis for new targeted drug therapy and an avenue for further investigation into the mechanisms underlying carcinogenesis of DKK1 in different cancer types.

LncRNA PCAT-1 plays an oncogenic role in epithelial ovarian cancer by modulating cyclinD1/CDK4 expression.

Epithelial ovarian cancer is one of the most common causes of gynecological cancer deaths. The knockdown of LncRNA PCAT-1 has been reported to suppress tumor growth in various kinds of cancers, including esophageal cancer, breast cancer, bladder cancer, and hepatocellular carcinoma. However, its function in epithelial ovarian cancer (EOC) is still unclear. In the present study, the expression of LncRNA PCAT-1 was investigated. The results indicate that the expression of LncRNA PCAT-1 is up-regulated in EOC tissues compared with non-cancer controls by reverse transcription-quantitative polymerase chain reaction analysis (RT-qPCR), and its higher expression is always associated with larger tumor sizes and advanced tumor grades in patients with EOC. In addition, silencing PCAT-1 in the EOC cell lines SKOV3 and OVCAR3 significantly inhibits cell proliferation, migration and invasion, which is also shown by cell cycle assays, as the proportion of cells in G0/G1 phase is dramatically increased after knocking down PCAT1. Finally, it is observed that PCAT-1's knockdown significantly decreased the levels of cyclin D1 and CDK4 protein expression. Taken together, LncRNA PCAT-1's oncogenic role in EOC by mediating cyclin D1/CDK4 is demonstrated, indicating it is a potential target for EOC treatment.

The SOX2OT/miR-194-5p axis regulates cell proliferation and mobility of gastric cancer through suppressing epithelial-mesenchymal transition.

Recent studies reported that long noncoding RNAs (LncRNAs) were involved in tumorigenesis of various human cancer types, including gastric cancer (GC) through targeting microRNAs (miRNAs/miRs). The present study investigated the biological functions of LncRNA SOX2 overlapping transcript (SOX2OT)/miR-194-5p axis and its underlying mechanism in the tumor progression of GC. The results showed that relative expression of LncRNA SOX2OT was highly upregulated while the expression of miR-194-5p was down-regulated in GC tissues and cell lines (MGC-803, SGC-7901, MKN-74). Knockdown of SOX2OT inhibited cell proliferation, invasion and migration of GC cells (MGC803, MKN-74) through reducing epithelial-mesenchymal transition (EMT). Moreover, miR-194-5p was predicted to be one of the targets of SOX2OT through bioinformatics analysis and was verified by luciferase reporter assay. miR-194-5p expression was negatively regulated by SOX2OT expression in GC cells and miR-194-5p inhibitor was found to counteract the inhibitory effects of SOX2OT short hairpin (sh)RNA on cell proliferation and mobility through enhancing EMT in GC cells. Taken together, the in vitro experiments revealed that knockdown of SOX2OT inhibited cell proliferation and mobility through suppressing EMT via targeting miR-194-5p in GC. In addition, results from in vivo experiments showed that knockdown of SOX2OT suppressed GC tumor growth and matrix metalloproteinase (MMP)-2 and MMP-9 expression through inhibiting EMT. Besides that, relative expression of miR-194-5p was increased in sh-SOX2OT group compared with sh-NC group. In summary, our study elucidated that the SOX2OT/miR-194-5p axis participated in the tumor progression of GC through regulation of EMT both in vitro and in vivo. Hence, targeting the SOX2OT/miR-194-5p axis may aid in establishing novel strategies for therapy of GC.