Gene Expression Profiling Interactive Analysis Databases Research Articles

Clinical significance of downregulated NISCH expression in skin cutaneous melanoma: Modulation of tumor cell invasion, migration, and EMT via PAK1 inhibition

ObjectiveThis study aimed to investigate the expression and functional role of NISCH in skin cutaneous melanoma (SKCM), exploring its association with clinical characteristics and its potential impact on human skin melanoma cell behavior. MethodsThe research assessed differential NISCH expression in SKCM tissues using the GEPIA (Gene Expression Profiling Interactive Analysis) database and validated these findings through immunohistochemical staining of 45 clinical samples. To affirm NISCH expression at the cellular level, three human skin melanoma cell lines (RPMI-7951, A375, MEL-5), and the human normal skin cell line HEMa underwent quantitative reverse transcription-polymerase chain reaction (qRT-PCR) and Western blotting. Transwell experiments evaluated the migration and invasion capabilities of RPMI-7951 and A375 cells post-transduction with NISCH or PAK1 lentiviral activation particles. Additionally, qRT-PCR analysis of epithelial-mesenchymal transition (EMT)-related gene expression (Vimentin, E-cadherin, N-cadherin) was conducted in A375 and RPMI-7951 cells. ResultsSKCM tissues exhibited significantly reduced NISCH expression compared to normal tissues. Immunohistochemical analysis revealed predominant nuclear localization of NISCH in melanoma cells, with reduced expression significantly correlating with sex, advanced stage, and lymph node metastasis. Melanoma cell lines displayed lower NISCH expression levels compared to normal skin cells. Functional experiments showcased that NISCH overexpression suppressed p-PAK1/PAK1, while PAK1 upregulation notably increased melanoma cell migration, invasion, and induced EMT. Remarkably, NISCH overexpression counteracted PAK1-induced effects on EMT, migration, and invasion in melanoma cells. ConclusionNISCH may significantly influence the aggressive behavior of SKCM cells via the PAK1 pathway, making it a potential therapeutic target for managing melanoma metastasis.

The RNA-binding protein sorbin and SH3 domain-containing 2 are transcriptionally regulated by specificity protein 1 and function as tumor suppressors in bladder cancer by stabilizing tissue factor pathway inhibitor.

Sorbin and SH3 domain-containing 2 (SORBS2) is anRNA-binding protein and has been implicated in the development of some cancers. However, its role in bladder cancer (BC) is yet to be established. The expression of SORBS2 in BC tissues was determined from the Gene Expression Omnibusand Gene Expression Profiling Interactive Analysisdatabases and collected paired tumor/normal samples. The effects of SORBS2 on BC cells were detected by CCK-8, colony formation, Transwell, dual-luciferase, RNA immunoprecipitation, chromatin immunoprecipitation, and DNA pull-down assays. In vivo, BC cell growth and metastasis were studied by a xenograft subcutaneous model and a tail-vein metastasis model. The results showed that SORBS2 expression was significantly decreased in BC tissues and cells. SORBS2 overexpression inhibited cell proliferation, migration, invasion, and epithelial-mesenchymal transitionin vitro and tumor growth and metastasis in vivo, while silencing SORBS2 produced the opposite effect. Mechanistically, we found that SORBS2 enhanced the stability of tissue factor pathway inhibitor (TFPI) mRNA via direct binding to its 3' UTR. Restoration of TFPI expression reversed SORBS2 knockdown-induced malignant phenotypes of BC cells. In addition, SORBS2 expression was negatively regulated by the transcription factor specificity protein 1 (SP1). Conversely, SORBS2 can be transcriptionally regulated by SP1 and inhibit BC cell growth and metastasis via stabilization of TFPI mRNA, indicating SORBS2 may be a promising therapeutic target for BC.

Over-Expression of EFNA2 in Lung Adenocarcinoma: EFNA2 Gene Expression Correlates with Shortened Survival

Background: The incidence of lung adenocarcinoma (LUAD) is increasing worldwide with different prognosis. Ephrin-A2（EFNA2), a member of the Eph/ephrin family, is associated with tumor progression. However, the correlations of EFNA2 with prognosis in LUAD remain unclear. The purpose of this article is to analyze the impact of EFNA2 on the prognosis of LUAD patients through TCGA, Oncomine, and GEPIA databases, and to explore its possible mechanisms. Methods: This article found a significant correlation between EFNA2 and shortened survival in LUAD patients through TCGA, Oncomine, and GEPIA database analysis. Therefore, we further invested the relationship between the expression and prognostic value of the EFNA2 gene in LUAD patients. Sequential data filtering (survival analysis, independent prognostic analysis, and clinicalcorrelation analysis) was performed. EFNA2 expression was analyzed by the Oncomine database and Tumor Immune Estimation Resource (TIMER). We evaluated the influence of EFNA2 on clinical prognosis using Kaplan-Meier plotter, the PrognoScan database and Gene Expression Profiling Interactive Analysis (GEPIA). The correlation between EFNA2 and cancer immune infiltrates was investigated by TIMER. In addition, correlations between EFNA2 expression and gene marker sets of immune infiltrates were analyzed by TIMER and GEPIA. In addition, gene enrichment analysis was performed by Metascape. Finally, a co-expression analysis was performed by the Oncomine database. Results: A cohort of LUAD patients showed that high EFNA2 expression was associated with poorer overall survival (OS), disease-free survival (DFS) by TCGA, and EFNA2 was significantly associated with stage in LUAD. In addition, EFNA2 expression was positively correlated with infiltrating levels of B cells and CD8+ T cells. Moreover, the differential expression of EFNA2 was significantly higher in lung adenocarcinoma compared with that in normal controls. Specifically, EFNA2 was positively associated with ADAMTSL5, REEP6, PCSK4, C19orf25, and ANAPC2. Conclusions: Our data indicate that EFNA2 is a potential diagnostic and prognostic biomarker and a promising molecular therapeutic target to attenuate LUAD progression.

Neuregulin 4 (Nrg4) cooperates with melatonin to regulate the PRL expression via ErbB4/Erk signaling pathway as a potential prolactin (PRL) regulator.

Neuregulin-4 (Nrg4) and melatonin play vital roles in endocrine diseases. However, there is little discussion about the function and potential mechanism of Nrg4 and melatonin in prolactin (PRL) regulation. The human normal pituitary data from Gene Expression Profiling Interactive Analysis (GEPIA) database was used to explore the correlation between NRG4 and PRL. The expression and correlation of NRG4 and PRL were determined by Immunofluorescence staining (IF) and human normal pituitary tissue microarray. Western Blot (WB) was used to detect the expression of PRL, p-ErbB2/3/4, ErbB2/3/4, p-Erk1/2, Erk1/2, p-Akt and Akt in PRL-secreting pituitary GH3 and RC-4B/C cells treated by Nrg4, Nrg4-small interfering RNA, Erk1/2 inhibitor FR180204 and melatonin. The expression of NRG4 was significantly positively correlated with that of PRL in the GEPIA database and normal human pituitary tissues. Nrg4 significantly increased the expression and secretion of PRL and p-Erk1/2 expression in GH3 cells and RC-4B/C cells. Inhibition of Nrg4 significantly inhibited PRL expression. The increased levels of p-Erk1/2 and PRL induced by Nrg4 were abolished significantly in response to FR180204 in GH3 and RC-4B/C cells. Additionally, Melatonin promotes the expression of Nrg4, p-ErbB4, p-Erk1/2, and PRL and can further promote the expression of p-Erk1/2 and PRL in combination with Nrg4. Further investigation into the function of Nrg4 and melatonin on PRL expression and secretion may provide new clues to advance the clinical control of prolactinomas and hyperprolactinemia.

Prognosis and clinical significance of Piezo2 in tumor: a meta-analysis and database validation.

The objective of this study is to assess the correlation between Piezo2 and tumors through a comprehensive meta-analysis and database validation. Case-control studies investigating the association between Piezo2 and tumors were obtained from various databases, including China National Knowledge Infrastructure (CNKI), SinoMed, Embase, Web of Science, The Cochrane Library, and PubMed. The search was performed from the inception of each database up until May 2023. Two researchers independently screened the literature, extracted data, and assessed the quality of the included studies. Metaanalysis of the included literature was conducted using Stata 12.0 software. Additionally, the Gene Expression Profiling Interactive Analysis (GEPIA) database predicted a correlation between Piezo2 expression and prognostic value in tumor patients. A total of three studies, involving a combined sample size of 392 participants, were included in the meta-analysis. The findings revealed that the expression level of Piezo2 in tumor patients was not significantly associated with age, gender, or tumor size. However, it was found to be positively correlated with lymphatic invasion (OR = 7.89, 95%CI: 3.96-15.73) and negatively correlated with invasion depth (OR = 0.17, 95%CI: 0.06-0.47), TNM stage (OR = 0.48, 95%CI: 0.27-0.87), and histological grade (OR = 0.40, 95%CI: 0.21-0.77). Confirming these findings, the GEPIA database indicated that high expression of Piezo2 was associated with poor prognosis of disease-free survival in patients with colon adenocarcinoma (HR = 1.6, P = 0.049) and gastric cancer (HR = 1.6, P = 0.017). Piezo2 may be associated with poor prognosis and clinicopathological parameters in tumor patients.

Spleen-Derived CCL9 Recruits MDSC to Facilitate Tumor Growth in Orthotopic Hepatoma Mice.

Objectives Spleen is involved in multiple diseases, the role of the spleen and spleen-derived factors in hepatocellular carcinoma (HCC) is still not clarified. Methods In the current study, a murine H22 orthotopic hepatoma model was established. Three groups were divided: normal mice, tumor-bearing mice with spleen-preserving, and tumor-bearing mice with splenectomy. Spleen and tumor weights were recorded by weeks 1 and 2. The proportion of myeloid-derived suppressor cell (MDSC) in peripheral blood and tumor tissue was detected using flow cytometry. Protein chip assay was used to compare the differential cytokines between normal liver supernatant and tumor supernatant. The common upregulated cytokines both in spleen and tumor were focused and analyzed using gene expression profiling interactive analysis (GEPIA) database. Enzyme-linked immunosorbent assay was performed to verify the chip result, and to examine CCL9 expression before and after splenectomy. Spleen MDSC was sorted using flow cytometry, and chemotaxis assay was performed to demonstrate whether CCL9 attracted spleen MDSC. Results The spleen enlarged during tumor progression, and compared with splenectomy group, there were faster tumor growth, shorter survival time, and higher proportions of MDSC in spleen-preserving group. Protein chip assay and GEPIA database revealed CCL9 was the most promising chemokine involved in HCC upregulated both in spleen and tumor tissue. CCL9 attracted MDSC in vitro, the level of CCL9 in tumor tissue was downregulated, and the percentage of MDSC was decreased after splenectomy. Conclusion The results demonstrate that CCL9 may be derived from spleen; it facilitated HCC growth via the chemotaxis of MDSC, targeting CCL9 may be a promising strategy in HCC treatment.

Echinacoside regulates PI3K/AKT/HIF-1α/VEGF cross signaling axis in proliferation and apoptosis of breast cancer

ContextEchinacoside (ECH) is a natural anti-cancer compound and is of great value in cancer treatment. However, the mechanism underlying this effect on breast cancer (BC) was unclear. ObjectiveTo explore the mechanism of ECH treating BC by network pharmacology and experimental validation. Materials & methodsSeveral databases were searched to screen potential targets of ECH and obtain information on targets related to BC. STRING was applied to construct a Protein-protein interaction (PPI) network. DAVID was applied for Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Gene Expression Profiling Interactive Analysis (GEPIA) was searched for the relationship between the expression profile and overall survival of major targets in normal breast and BC tissues. Finally, the results of network pharmacology analysis were validated by experiments. ResultsSeventeen targets of ECH overlapped with targets in BC. Ten hub targets were determined through PPI. By GO and KEGG analysis 15 entries and 25 pathways were obtained, in which phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT), hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) played greater roles. Validation of key targets in the GEPIA database showed that PIK3R1 and PIK3CD remained consistent with the results of the study. Experiments in vitro showed ECH inhibited proliferation, induced apoptosis and reduced mRNA levels and protein expression of PI3K, AKT, hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA) in MCF-7 cells. Furthermore, experiments in vivo revealed that ECH significantly reduced tumor growth, promoted apoptosis and decreased the related mRNA levels and protein expression, suggesting ECH works on BC by regulating PI3K/AKT/HIF-1α/VEGF signaling pathway. Discussion & conclusionIn summary, ECH played an important role in anti-BC by regulating PI3K/AKT/HIF-1α/VEGF signaling pathway. Furthermore, ECH had multi-target and multi-pathway effects, which may be a promising natural compound for treating BC.

RUNX1 promotes proliferation and migration in non-small cell lung cancer cell lines via the mTOR pathway.

RUNX1, a member of the RUNX family of metazoan transcription factors, participates in the regulation of differentiation, proliferation, and other processes involved in growth and development. It also functions in the occurrence and development of tumors. However, the role and mechanism of action of RUNX1 in non-small cell lung cancer (NSCLC) are not yet clear. We used a bioinformatics approach as well as in vitro and in vivo assays to evaluate the role of RUNX1 in NSCLC as the molecular mechanisms underlying its effects. Using the TCGA, GEO, GEPIA (Gene Expression Profiling Interactive Analysis), and Kaplan-Meier databases, we screened the differentially expressed genes (DEGs) and found that RUNX1 was highly expressed in lung cancer and was associated with a poor prognosis. Immunohistochemical staining based on tissue chips from 110 samples showed that the expression of RUNX1 in lung cancer tissues was higher than that in adjacent normal tissues and was positively correlated with lymph node metastasis and TNM staging. In vitro experiments, we found that RUNX1 overexpression promoted cell proliferation and migration functions and affected downstream functional proteins by regulating the activity of the mTOR pathway, as confirmed by an analysis using the mTOR pathway inhibitor rapamycin. In addition, RUNX1 affected PD-L1 expression via the mTOR pathway. These results indicate that RUNX1 is a potential therapeutic target for NSCLC.

Identification of HOXB9 based on comprehensive bioinformatics analysis for predicting prognosis of head and neck squamous cell carcinoma.

To evaluate the correlation between HOXB9 expression, and the prognosis and immune infiltration in head and neck squamous cell carcinoma (HNSCC). Pan-cancer HOXB9 expression was analyzed through TIMER2.0. The HOXB9 expression data of HNSCC and normal tissues were compared using the gene expression profiling interactive analysis (GEPIA) and the cancer genome atlas (TCGA) databases. The University of Alabama at Birmingham (UALCAN) database was used to analyze the relative expression of HOXB9 in HNSCC subgroups based on clinicopathological features, including cancer stage, tumor grade and lymph node stage. Survival analysis was performed using GEPIA, TCGA-Portal, Kaplan-Meier Plotter, and UALCAN databases. The genes co-expressed with HOXB9 were identified using TCGA data, and functionally annotated by GO and KEGG analyses. Protein-protein interaction network was constructed using the STRING database and Cytoscape 3.7.1. Single-sample gene set enrichment analysis was performed to assess the correlation between HOXB9 and immune infiltration based on TCGA data. TIMER 2.0 database was used to explore the correlation between HOXB9 expression and immune infiltration multiple cancers. HOXB9 mRNA is elevated in multiple cancers, and was upregulated in HNSCC tissues compared to non-paired (P < .05 in GEPIA; P < .0001 in TCGA) as well as paired (P < .0001 in TCGA) normal tissues. In addition, HOXB9 expression was positively correlated with tumor malignancy in the GEPIA and UALCAN databases (P < .05), and negatively with patient prognosis in both databases (P < .05). High HOXB9 expression was associated with increased infiltration of aDCs, NK CD56bright cells, NK cells, and Th2 cells (P < .05), while low HOXB9 expression was associated with an increase in the proportion of DCs, iDCs, mast cells, neutrophils, and Th17 cells (P < .05). HOXB9 likely functions as an oncogene in HNSCC by disrupting the immune landscape, and is a promising prognostic biomarker and therapeutic target.

GPX2 acts as an oncogene and cudraflavone C has an anti-tumor effect by suppressing GPX2-dependent Wnt/β-catenin pathway in colorectal cancer cells.

Colorectal carcinoma (CRC) is a common cancer associated with poor prognosis, and cudraflavone C (Cud C) is a natural flavonol with reported anti-CRC capacity. However, the precise mechanisms underlying the anti-CRC effect require further demonstration. The aim of present study was to evaluate the impact of Cud C on the cell viability and apoptosis of CRC cells and to determine the underlying mechanisms. The Human Protein Atlas (THPA) and Gene Expression Profiling Interactive Analysis (GEPIA) databases were used to analyze the expression status of glutathione peroxidase 2 (GPX2) in CRC. Cell viability was examined using cell counting kit-8 (CCK-8) assay. Flow cytometry was utilized to evaluate apoptosis. The levels of gene transcription and protein expression of GPX2, caspase-3, cleaved caspase-3), β-catenin, and c-Myc were determined by RT-qPCR and Western blotting. Our results showed that GPX2 was overexpressed in CRC as compared to normal tissue and the extent of GPX2 overexpression is greatest in CRC when compared with other cancers according to GEPIA and THPA databases. GPX2 knockdown significantly suppressed the cell viability, induced apoptosis of CRC cell lines, and restrained the activity of Wnt/β-catenin pathway. Cud C treatment decreased cell viability, induced apoptosis in CRC cell lines, and diminished the expression level of GPX2-dependent activation of Wnt/β-catenin pathway, while such effects can be abolished by GPX2 overexpression. In conclusion, Cud C suppressed GPX2-dependent Wnt/β-catenin pathway to exert anti-CRC function.

Identification of potential DNA methylation biomarkers related to diagnosis in patients with bladder cancer through integrated bioinformatic analysis

BackgroundBladder cancer (BLCA) is one of the most common malignancies among tumors worldwide. There are no validated biomarkers to facilitate such treatment diagnosis. DNA methylation modification plays important roles in epigenetics. Identifying methylated differentially expressed genes is a common method for the discovery of biomarkers.MethodsBladder cancer data were obtained from Gene Expression Omnibus (GEO), including the gene expression microarrays GSE37817( 18 patients and 3 normal ), GSE52519 (9 patients and 3 normal) and the gene methylation microarray GSE37816 (18 patients and 3 normal). Aberrantly expressed genes were obtained by GEO2R. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed using the DAVID database and KOBAS. Protein-protein interactions (PPIs) and hub gene networks were constructed by STRING and Cytoscape software. The validation of the results which was confirmed through four online platforms, including Gene Expression Profiling Interactive Analysis (GEPIA), Gene Set Cancer Analysis (GSCA), cBioProtal and MEXPRESS.ResultsIn total, 253 and 298 upregulated genes and 674 and 454 downregulated genes were identified for GSE37817 and GSE52519, respectively. For the GSE37816 dataset, hypermethylated and hypomethylated genes involving 778 and 3420 genes, respectively, were observed. Seventeen hypermethylated and low expression genes were enriched in biological processes associated with different organ development and morphogenesis. For molecular function, these genes showed enrichment in extracellular matrix structural constituents. Pathway enrichment showed drug metabolic enzymes and several amino acids metabolism, PI3K-Akt, Hedgehog signaling pathway. The top 3 hub genes screened by Cytoscape software were EFEMP1, SPARCL1 and ABCA8. The research results were verified using the GEPIA, GSCA, cBioProtal and EXPRESS databases, and the hub hypermethylated low expression genes were validated.ConclusionThis study screened possible aberrantly methylated expression hub genes in BLCA by integrated bioinformatics analysis. The results may provide possible methylation-based biomarkers for the precise diagnosis and treatment of BLCA in the future.

Preliminary study of PPARA regulate the ferroptosis of hepatocellular carcinoma to prevent disease deterioration

To explore whether PPARA is involved in the process of ferroptosis in hepatoma cells, peroxisome proliferator activated receptor (PPARA) was comprehensively analyzed in hepatocellular carcinoma (HCC) through public database and experimental data, including the expression, the functions and the potential roles of tumor progression. The research design is experimental research,data analysis based on bioinformatics and cell experiment. From January 2022 to August 2022, relevant cell experiments were conducted in the Basic Medical Laboratory of the General Hospital of the Southern Theatre of the Chinese People's Liberation Army. The expression and the correlation with clinicopathologic features of PPARA in HCC were analyzed by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. To study the protein expression of PPARA in HCC and normal tissues through the Human Protein Atlas (HPA). The protein-protein interaction (PPI) network between PPARA and the core factor of ferroptosis was constructed based on Search Tool for the Retrival of Interacting Genes/Protein (STRING) database, then, the correlation between PPARA and the core gene Glutamate-cysteine Ligase Catalytic Subunit (GCLC) was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA). Assessed the expression of PPARA in HCC cell lines SK-HEP-1, SMMC-7721, MHCC-97H, BEL-7402 and normal liver cell L02 by Western Blot (WB) and the changes of PPARA expression after 48h treatment with ferroptosis inducer Erastin were observed. Single factor analysis of variance was used to compare the expression of PPARA between groups in GEPIA database. The expression of PPARA in GSE25097 and GSE112790 data was compared by rank sum test. Survival analysis was performed using time series test method. The difference of PPARA expression between clinical and pathological features was compared using the Kruskal-Wallis test. The correlation between the expression of GCLC and PPARA was compared by the method of Spearman correlation. The expression of PPARA in cell lines was compared by paired T test. The results showed that the RNA and protein expression of PPARA in HCC was lower than that in normal tissues (P<0.05). PPARA alterations were correlated with patient clinicopathological features and prognosis (P<0.05). The PPI constructed by STRING database suggests that PPARA interact with the key factors of ferroptosis, such as NFE2 like bZIP transcription factor 2 (NFE2L2), Heme Oxygenase 1 (HMOX1), Tumor Protein P53 (TP53), GCLC, Dipeptidyl Peptidase 4 (DPP4), Citrate Synthase (CS), Arachidonate 15-Lipoxygenase (ALOX15) and Acyl-CoA Synthetase Long Chain Family Member 4 (ACSL4). Furthermore, the PPARA was significantly associated with GCLC validated via GEPIA database(R=0.6, P<0.05). The expression of PPARA increased after treatment with ferroptosis inducer Erastin for 48 h by WB. In conclusion, the expression of PPARA is lower in HCC with a poor prognosis. PPARA interacts with GCLC in regulating ferroptosis in HCC.

Role of protein tyrosine phosphatase receptor type M in epithelial ovarian cancer progression

BackgroundEpithelial ovarian cancer (EOC) is often diagnosed at advanced stages with low survival rates. Protein tyrosine phosphatase receptor type M (PTPRM) is involved in cancer development and progression; however, its role in EOC remains unclear. In this study,we aimed to detect PTPRM expression in ovarian epithelial tumors, analyze its relationship with the clinicopathological features and survival prognosis of patients with EOC, and provide a theoretical basis for new targets for EOC treatment. Fifty-seven patients with EOC treated at our hospital between January 2012–January 2014 were included; along with 18 borderline and 30 benign epithelial ovarian tumors and 15 normal ovarian and uterine tube tissue samples from patients surgically treated at our hospital during the same period. PTPRM expression was immunohistochemically detected, and we analyzed its relationship with clinicopathological features and prognosis. Associations between PTPRM expression and survival prognosis of patients with EOC were analyzed using the Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier Plotter databases.ResultsPTPRM had the highest expression rates in normal ovarian and uterine tube tissues, followed by benign and borderline epithelial ovarian tumors; the lowest positive expression rate was observed in EOC tumors. PTPRM expression differed significantly among groups (P < 0.05). The positive PTPRM expression rate significantly decreased with age, progressing clinical stage, and tumor recurrence, and the larger the mass diameter, the higher the positive PTPRM expression rate. PTPRM expression was significantly lower in ovarian cancer compared with that in normal tissues in the GEPIA database (P < 0.05). The overall survival (OS) and disease-free survival(DFS) rates were higher in the PTPRM high-expression group, with statistically significant (P < 0.05) and insignificant (P > 0.05) differences, respectively. The OS rate of the high-expression group compared with the low-expression group in the Kaplan–Meier Plotter database was higher, although without statistical significance (P > 0.05), and progression-free survival(PFS) was higher with statistical significance (P < 0.05).ConclusionPTPRM expression was low in patients with EOC, and the PTPRM positive-expression rate significantly decreased with progressing stages of EOC and tumor recurrence, suggesting that PTPRM acts as a tumor suppressor in EOC progression. Negative PTPRM expression may predict poor clinical outcomes in patients with EOC.

SPTBN2 regulates endometroid ovarian cancer cell proliferation, invasion and migration via ITGB4‑mediated focal adhesion and ECM receptor signalling pathway.

Ovarian cancer is as a major contributor to gynaecologic death globally. The present study aimed to investigate the regulatory role of spectrin β non-erythrocytic 2 gene (SPTBN2) in endometroid ovarian cancer and its mechanism of action. According to the Gene Expression Profiling Interactive Analysis (GEPIA) database, SPTBN2 expression is elevated in ovarian cancer tissues and higher SPTBN2 expression indicated a worse prognosis. The present study assessed SPTBN2 mRNA and protein expression levels by reverse transcription-quantitative PCR and western blotting, respectively. Cell viability, proliferation, migration and invasion were assessed with Cell Counting Kit-8, 5-ethynyl-2'-deoxyuridine incorporation, wound healing and Transwell assays, respectively. SPTBN2 expression was notably enhanced in ovarian cancer cell lines, especially in A2780 cells compared with HOSEPiC cells (P<0.001). Following transfection with small interfering (si)RNA targeting SPTBN2, the viability, proliferation, migration and invasion of A2780 cells were decreased compared with those of A2780 cells transfected with siRNA-NC (P<0.001). Gene Set Enrichment Analysis database revealed that SPTBN2 was primarily enriched in 'focal adhesion' and 'extracellular matrix (ECM)-receptor interaction', whereas SPTBN2 was significantly associated with integrin β4 (ITGB4) in the GEPIA database. In addition, rescue experiments were performed to determine the mechanism of SPTBN2 in endometroid ovarian cancer. ITGB4 overexpression reversed the inhibitory effects of the SPTBN2 knockdown on viability, proliferation, migration and invasion of A2780 cells (P<0.05). The impacts of SPTBN2 on the expression of focal adhesion and downstream ECM receptor signalling-related proteins, including Src and p-FAK/FAK, were significantly reversed by ITGB4 overexpression (P<0.01). Collectively, SPTBN2 may regulate endometroid ovarian cancer cell proliferation, invasion and migration through the ITGB4-mediated focal adhesion and ECM receptor signalling pathway.

Clinicopathological and prognostic significance of SPARC expression in gastric cancer: A meta‑analysis and bioinformatics analysis.

Secreted protein acidic and rich in cysteine (SPARC) is a member of the extracellular matrix glycoprotein family that binds to calcium ions. It may bind to a variety of proteins in the extracellular matrix and also compete with cell membrane surface receptors for growth. In the present study, the relationship between SPARC expression in gastric cancer tissues and the clinicopathological characteristics and prognosis of patients with gastric cancer were systematically evaluated. A meta-analysis and bioinformatics analysis were performed using the PubMed, Chinese National Knowledge Infrastructure, Kaplan-Meier (KM)-plotter, The Cancer Genome Atlas (TCGA), Gene Expression Profiling Interactive Analysis (GEPIA), University of ALabama at Birmingham CANcer (UALCAN), Human Protein Atlas (HPA) and Timer databases. SPARC was mainly expressed in tumor mesenchymal cells. The meta-analysis indicated that SPARC expression was higher in gastric cancer tissues than in normal tissues. SPARC was associated with the degree of differentiation and distant metastasis. K-M plotter results indicated that high SPARC expression was negatively associated with overall survival, post-progression survival and progression-free survival rates of patients. According to the Oncomine, GEPIA, UALCAN and HPA databases, SPARC mRNA and protein expression was upregulated in gastric cancer vs. normal tissues and was negatively associated with poor patient prognosis. In the TCGA database, univariate analysis indicated that lymph node metastasis and distant metastasis were associated with the prognosis of patients with gastric cancer. Cox multifactorial analysis suggested that high SPARC expression, age and distant metastasis were important factors affecting the survival time of patients with gastric cancer. Analysis with the Timer database indicated that SPARC was closely associated with the proportion of 7 immune-cell infiltrates in gastric cancer. These findings indicated that high expression of SPARC may be a potential marker of tumorigenesis and metastasis in patients with gastric cancer.

Abstract 534: PRMT5 inhibition as a therapeutic strategy for KRAS mutant CRC: downstream mediators of the PRMT5-KRAS crosstalk

Abstract Despite decades of research, there are still no effective targeted treatments for the nearly 45% of colorectal cancer (CRC) patients harboring a mutation in their KRAS gene. Protein Arginine Methyltransferase 5 (PRMT5) is an epigenetic regulator undergoing clinical trials as a potential therapeutic target for cancer. Our group has previously reported that PRMT5 is overexpressed in KRAS mutant CRC when compared to KRAS wild-type (WT) CRC, and that PRMT5 inhibition exhibited greater therapeutic efficacy in KRAS mutant CRC when compared to KRAS WT CRC. We therefore proposed that PRMT5 may be a strong therapeutic target for KRAS mutant CRC, and that PRMT5 and KRAS may crosstalk. In this study, we investigated several key downstream signal transduction proteins that may be involved in mediating the potential crosstalk between PRMT5 and KRAS. This is important, as these key intermediate proteins may be strong therapeutic targets for inhibition, as well as valuable therapeutic targets for combination therapy along with PRMT5 inhibitors. We first conducted a literature review to determine which key downstream proteins may be involved in mediating the potential crosstalk between PRMT5 and KRAS. Our initial findings indicated that MYC, p65/RELA, TP53, P21/CDKN1A, ELF1, E2F1, and EIF4E may be key downstream proteins involved in mediating the potential crosstalk between PRMT5 and KRAS. We next used the STRING database to determine which of the aforementioned proteins have demonstrated interactions with PRMT5 and KRAS. We found that PRMT5 and KRAS both interact with MYC, p65/RELA, TP53, P21/CDKN1A, E2F1, and EIF4E with an interaction score &amp;gt; 0.150. We then used the Gene Expression Profiling Interactive Analysis (GEPIA) database to analyze the RNA-Seq data of CRC patients from The Cancer Genome Atlas (TCGA) database. We first used the GEPIA database to determine which proteins are overexpressed in CRC patient tumor samples compared to normal colon and rectum patient samples. We observed that MYC, TP53, E2F1, and EIF4E are all over 2-fold overexpressed in CRC patient tumor samples compared to normal colon and rectum patient samples (q &amp;lt; 0.01). We next used the GEPIA database to determine which proteins have an expressional correlation with PRMT5 and KRAS in CRC patient tumor samples. We found that MYC, E2F1, and EIF4E are all positively correlated with PRMT5 and KRAS with an R-Value &amp;gt; 0.70 and a P-Value &amp;lt; 0.01 in CRC patient tumor samples. Our study thus showcases the key downstream signal transduction proteins that may be involved in mediating the potential crosstalk between PRMT5 and KRAS. These findings are significant, as these key intermediate proteins may be strong therapeutic targets for inhibition, as well as strong therapeutic targets for a PRMT5 combination therapy. Additional research is currently underway to outline the molecular processes behind MYC, E2F1, and EIF4E’s interactions with both PRMT5 and KRAS. Citation Format: David Shifteh, Tzuriel Sapir, Moshe Pahmer, Sanjay Goel, Radhashree Maitra. PRMT5 inhibition as a therapeutic strategy for KRAS mutant CRC: downstream mediators of the PRMT5-KRAS crosstalk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 534.

Prognostic Significance of the CXCLs and Its Impact on the Immune Microenvironment in Ovarian Cancer.

The chemokine (C-X-C motif) ligand (CXCL) family in tumor tissue is closely related to tumor growth, metastasis, and survival. However, the differential expression profile and prognostic value of the CXCLs in ovarian cancer (OC) have not been elucidated. Therefore, we studied the expression levels and mutations of CXCLs in OC patient in TCGA and various public databases. The expression differences of CXCLs in OC cancer tissues and normal tissues were compared through the Gene Expression Profiling Interactive Analysis (GEPIA) database. The effect of CXCLs on OC prognosis was analyzed using the Kaplan-Meier curves in GEPIA database. The impact of CXCLs on immune infiltration and clinicopathological outcomes in OC was assessed using the TIMER algorithm. Compared with normal tissues, we found that eight CXCLs were significantly differentially expressed in OC. The expression levels of CXCL9 (P = 0.0201), CXCL11 (P = 0.0385), and CXCL13 (P = 0.0288) were significantly associated with tumor stage. CXCL13 was the only gene that significantly affected both disease-free survival (DFS) and overall survival (OS) in OC, and higher CXCL13 transcript levels implied longer DFS and OS. Although there was no significant impact on DFS, CXCL10 (P = 0.0079) and CXCL11 (P = 0.0011) expression levels had a significant effect on OS in OC. At the same time, CXCLs were significantly associated with several immune-infiltrating cells in OC tissues. The CXCLs were significantly associated with one or more immune-infiltrating cells in OC tissue. CXCL13 was differentially expressed in OC and significantly affected the prognosis of patients and was a potential marker of OC prognosis.

Overexpression of HMGB3 and its prognostic value in breast cancer.

High mobility group protein B3 (HMGB3) is abundantly expressed in a number of malignancies, contributing to tumor cell growth and predicting poor outcomes. More research on the connection between HMGB3 and breast cancer is needed. The prognostic significance of HMGB3 in breast cancer was examined and validated in this study. Using The Cancer Genome Atlas (TCGA) database RNA sequencing and clinical data, we investigated the associations between HMGB3 expression and tumor mutations, prognosis, and immune infiltration in breast cancer. The Gene Expression Profiling Interactive Analysis (GEPIA), Tumor Immune Estimation Resource (TIMER), breast cancer gene-expression miner (bc-GenExMiner), UALCAN, OncoLnc, cBio Cancer Genomics Portal (cBioPortal), and LinkedOmics databases were applied to examine the levels of expression, mutation, coexpression, and immune correlation of HMGB3 in breast cancer. cBioPortal and the Database for Annotation, Visualization, and Integrated Discovery (DAVID) were used for coexpression and enrichment analyses, respectively. Experimental tests and a separate cohort of breast cancer patients in our center were used for validation. To determine independent risk factors affecting breast carcinoma prognosis, multivariate Cox regression analysis was performed. The Kaplan-Meier method was applied to analyze the connection between HMGB3 expression and overall survival time in breast cancer. Pan-cancer investigation using the GEPIA and UALCAN databases revealed a high level of HMGB3 expression in different malignancies, including breast cancer. HMGB3 might be a potential diagnostic biomarker, according to the receiver operating characteristic (ROC) curve (AUC=0.932). And immunohistochemistry confirmed higher HMGB3 protein expression in breast cancer tissues in clinical samples. Experimental tests also showed that breast cancer cells have higher expression of HMGB3, and knockdown of HMGB3 can promote the proliferation of breast cancer cells and increase sensitivity to chemotherapy. Human epidermal growth factor receptor 2 (HER2), Nottingham Prognostic Index (NPI), basal-like status, nodal status (N+), triple-negative status, and Scarff-Bloom-Richardson (SBR) grade all showed positive correlations with HMGB3 expression. Conversely, HMGB3 expression was negatively associated with the expression of estrogen receptor (ER) and progesterone receptor (PR) in breast cancer. Breast cancer patients with high HMGB3 expression had poor overall survival, which was validated by an analysis of a separate cohort of breast cancer patients in our center. Cox regression analysis identified high HMGB3 expression as an independently associated risk factor for breast carcinoma. The amount of immunological infiltration was substantially linked with the high expression of HMGB3. The chromosome centromeric region, ATPase activity, and the cell cycle are critical areas where HMGB3 is involved, according to enrichment analysis. Therefore, we suspected that HMGB3 might be a potential biomarker for detecting and treating breast carcinoma. Breast cancer tissues had higher HMGB3 expression than normal breast tissues. HMGB3 overexpression may serve as an indicator for poor breast cancer outcomes.

ATAD2 Upregulation Promotes Tumor Growth and Angiogenesis in Endometrial Cancer and Is Associated with Its Immune Infiltration.

Endometrial cancer is one of the three major gynecologic malignancies, and its incidence continues to rise. ATPase family AAA structural domain-containing protein 2 (ATAD2) is an ATPase protein, which is an independent factor for poor prognosis in endometrial cancer. However, its role in the disease is yet to be determined. The Tumor IMmune Estimation Resource (TIMER) database was used to assess ATAD2 expression in pan-cancer, and the relevance of ATAD2 expression in Uterine Corpus Endometrial Carcinoma (UCEC) in clinical settings was obtained using Gene Expression Profiling Interactive Analysis (GEPIA) and UALCAN analysis. In addition, the Human Protein Atlas database was used to assess ATAD2 protein expression in UCEC. Furthermore, in vitro molecular biology and in vivo functional experiments were employed to ascertain the effect of ATAD2 expression on tumor angiogenesis and tumor growth. UALCAN was used to screen for ATAD2 coexpressed genes, and Sangerbox was utilized to perform Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of these coexpressed genes. Finally, the TIMER, Tumor Immune System Interaction and Drug Bank (TISIDB), and GEPIA databases were used to analyze the relationship between ATAD2 and immune infiltration. ATAD2 is highly expressed in a variety of tumors, and in UCEC, it plays the role of a protooncogene. Basic experiments revealed that ATAD2 promotes vascular endothelial growth factor expression in endometrial cancer and affects tumor growth and angiogenesis. In addition, GO and KEGG enrichment analyses showed that ATAD2-associated genes were chiefly enriched in certain signaling pathways, such as herpes simplex virus 1 infection and that ATAD2 was associated with immune infiltration in UCEC. Our findings suggest that ATAD2 promotes tumor growth and angiogenesis in endometrial cancer. Furthermore, ATAD2 is associated with immune infiltration and is a potential diagnostic and therapeutic target.

Identification of immuno-infiltrating MAP1A as a prognosis-related biomarker for bladder cancer and its ceRNA network construction.

Approximately 75% of bladder cancer occurrences are of the non-muscle-invasive type. The estimated five-year survival rate is 26%-55%. Currently, there is no reliable biomarker available for early diagnosis and prognosis of bladder cancer. The present study aims to identify a biomarker using bioinformatic approaches to provide a new insight in clinical research for early diagnosis and prognosis of bladder cancer. Clinical data and a transcriptome of bladder cancer were obtained from TCGA, GEO, GETx, and UCSC Xena. The differential expressed gene (DEG) analysis, weighted gene co-expression network analysis (WGCNA), and survival analysis using the Kaplan-Meier and Cox proportional-hazards models were used to identify the Microtubule-associated Proteins 1A (MAP1A). on overall survival (OS) and disease-free survival (DFS) was analyzed using GEPIA and GETx databases. The TIMER 2.0 database predicted the correlation between MAP1A and immunocytes and immune checkpoints. Target prediction of the regulated competing endogenous RNAs (ceRNAs) network of MAP1A was performed using starBase and TargetScan. Cystoscope v3.7.2 software was used to visualize the ceRNA coexpression network. The R programming language v4.0.2 was applied as an analytic tool. Gene expression of MAP1A verified by RT-qPCR. The low expression of MAP1A was verified in bladder cancer tissues and bladder cancer cell lines SW780 and 5637.P < 0.001 were obtained by Kaplan-Meier survival analysis and Cox proportional hazards model, with a hazard ratio (HR) of 1.4. Significant correlations between MAP1A and OS (P < 0.001, HR = 1.9) as well as DFS (P < 0.05, HR = 1.7) in bladder cancer were identified through gene expression profiling interactive analysis (GEPIA), indicating MAP1A may be a high-risk factor. Significant correlation in single copy-number variation of MAP1A gene with CD8+ T cells, and myeloid dendritic cells (MDCs) (P < 0.05) was noted. MAP1A expression was shown to be significantly correlated with the amount of CD4+ T cells and CD8+ T cells, MDCs, macrophages, and neutrophils in a statistically significant positive manner (P < 0.001). However, the MAP1A expression demonstrated a strong negative connection with B cells (P < 0.001). Except for macrophage M1 genes IRF5 and PTGS2, MAP1A expression was significantly correlated with the gene levels in immunocytes such as CD4+ T cells, CD8+ T cells, B cells, dendritic cells (DCs), macrophages, and neutrophils (Cor > 0.2, P < 0.001), as well as immune checkpoint related genes including cytotoxic t-lymphocyte-associated protein 4 (CTLA-4), programmed death 1 (PD-1), programmed death ligand 1 (PD-L1) (P < 0.001). Finally, we predicted that the MAP1A-interacting miRNA was miR-34a-5p, and the MAP1A endogenous competing RNAs were LNC00667, circ_MAP1B, and circ_MYLK, respectively. These findings support the need for further studies on the mechanism underlying the pathogenesis of this disease. MAP1A is considered as a prospective biomarker for early diagnosis, therapeutic observation, and prognosis analysis in bladder cancer.