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Comprehensive Analysis of E2F Family Members in Human Gastric Cancer.

ABSTRACT: Gastric cancer (GC) is the second most common cancer and the third most frequent cause of cancer-related deaths in China. E2Fs are a family of transcription factors reported to be involved in the tumor progression of various cancer types; however, the roles of individual E2Fs are still not known exactly in tumor progression of GC. In this study, we examined the expression of E2Fs to investigate their roles in tumor progression in GC patients using multiple databases, including ONCOMINE, GEPIA2, Kaplan-Meier plotter, cBioPortal, Metascape, LinkedOmics, GeneMANIA, STRING and UCSC Xena. We also performed real-time polymerase chain reaction (RT-PCR) to validate the expression levels of individual E2Fs in several GC cell lines. Our results demonstrated that the mRNA levels of E2F1/2/3/5/8 were significantly higher both in GC tissues and cell lines. The expression levels of E2F1 and E2F4 were correlated with poor overall survival (OS), decreased post-progression survival (PPS), and decreased progression-free survival (FP) in patients with GC. However, overexpression of E2F2, E2F5, E2F7 and E2F8 is significantly associated with disease-free survival and overall survival in patients with GC. In addition, higher E2F3 and E2F6 mRNA expression was found to increase GC patients' OS and PPS. 224 of 415 patients with STAD (54%) had gene mutations that were associated with longer disease-free survival (DFS) but not OS. Cell cycle pathway was closely associated with mRNA level of more than half of E2Fs (E2F1/2/3/7/8). There were close and complicated interactions among E2F family members. Finally, our results indicated the gene expressions of E2Fs had a positive relationship with its copy numbers. Taken together, E2F1/2/3/5/8 can serve as biomarkers for GC patients with high prognostic value for OS of GC patients or therapeutic targets for GC.

SUBMITTER: Li S

PROVIDER: S-EPMC8438234 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Gastric cancer (GC) is one of the most common and poor prognosis malignancy in the world. The Family with sequence similarity 83 (FAM83) comprises of eight members of A-H. Accumulating evidence confirmed important roles for FAM83 family in tumorigenesis and progression. However, the prognostic values of FAM83 family in GC still have not been clarified. Methods: ONCOMINE, UALCAN, GEPIA, THE HUMAN PROTEIN ATLAS, Kaplan-Meier Plotter, cBioPortal, DAVID, STRING and TIMER databases and R software were adopted in this study. Results: In this study, we demonstrated that the mRNA levels of FAM83 B/C/D/H were significantly up-regulated in stomach adenocarcinoma (STAD), but the protein level of FAM83G/H were remarkable lowly in STAD. Next, FAM83C/D/G/H were significantly associated with tumor stages in STAD patients. Then, the mutation rate of FAM83 family members in STAD patients was 46%, and the highest mutation rate was FAM83H (23%). Furthermore, the functions of FAM83 family and their 259 co-expression genes were primarily related to Shigellosis, RNA degradation and Ribosome biogenesis in eukaryotes pathway. Besides, we have established the prognostic model of FAM83 family in STAD, including the prognostic model of STAD patients (FAM83C/D/G), STAD with lymph node metastasis (FAM83C/D/G/H) and STAD with ERBB2 high expression (FAM83G/H). FAM83C/D high expression with a poor prognosis, while FAM83G/H high expression with a favorable prognosis of STAD. Additionally, we found that the expression of FAM83C/D/G/H were significantly correlated with the infiltration of six types of immune cells [B cells, CD8+T cells, CD4+T cells, macrophages and Myeloid dendritic cells (DC)], whereas CD4+T cells and Macrophage cells have higher risk scores (HR > 1) when FAM83C lowly expression and FAM83D highly expression. The risk score of NK cells was significantly reduced when FAM83G lowly expression and FAM83H highly expression (HR < 1). Conclusion: These findings suggested that FAM83C/D/G/H might play key roles in STAD tumorigenesis and progression, and FAM83C/D might be risk factors but FAM83G/H might be favorable prognostic factors for STAD patients. In addition, CD4+T cells and Macrophage cells may be the promoters of FAM83D in progression of STAD, while NK cells may promote the protective effect of FAM83H on STAD patients.

Project description:BackgroundFibroblast growth factor receptors (FGFRs) modulate numerous cellular processes in tumor cells and tumor microenvironment. However, the effect of FGFRs on tumor prognosis and tumor-infiltrating lymphocytes in gastric cancer (GC) remains controversial.MethodsThe expression of four different types of FGFRs was analyzed via GEPIA, TCGA-STAD, and GTEX databases and our 27 pairs of GC tumor samples and the adjacent normal tissue. Furthermore, the Kaplan-Meier plot and the TCGA database were utilized to assess the association of FGFRs with clinical prognosis. The R software was used to evaluate FGFRs co-expression genes with GO/KEGG Pathway Enrichment Analysis. In vitro and in vivo functional analyses and immunoblotting were performed to verify FGFR4 overexpression consequence. Moreover, the correlation between FGFRs and cancer immune infiltrates was analyzed by TIMER and TCGA databases. And the efficacy of anti-PD-1 mAb treatment was examined in NOG mouse models with overexpressed FGFR1 or FGFR4.ResultsThe expression of FGFRs was considerably elevated in STAD than in the normal gastric tissues and was significantly correlated with poor OS and PFS. ROC curve showed the accuracy of the FGFRs in tumor diagnosis, among which FGFR4 had the highest ROC value. Besides, univariate and multivariate analysis revealed that FGFR4 was an independent prognostic factor for GC patients. According to a GO/KEGG analysis, the FGFRs were implicated in the ERK/MAPK, PI3K-AKT and extracellular matrix (ECM) receptor signaling pathways. In vivo and in vitro studies revealed that overexpression of FGFR4 stimulated GC cell proliferation, invasion, and migration. In addition, FGFR1 expression was positively correlated with infiltrating levels of CD8+ T-cells, CD4+ T-cells, macrophages, and dendritic cells in STAD. In contrast, FGFR4 expression was negatively correlated with tumor-infiltrating lymphocytes. Interestingly, overexpression of FGFR1 in the NOG mouse model improved the immunotherapeutic impact of GC, while overexpression of FGFR4 impaired the effect. When combined with an FGFR4 inhibitor, the anti-tumor effect of anti-PD-1 treatment increased significantly in a GC xenograft mouse model with overexpressed FGFR4.ConclusionsFGFRs has critical function in GC and associated with immune cell infiltration, which might be a potential prognosis biomarker and predictor of response to immunotherapy in GC.

Project description:AimTo evaluate the effects of the proteasome inhibitor bortezomib (BZB) on E2Fs and related genes in hepatocellular carcinoma (HCC) cells.MethodsThe mRNA levels of the E2F family members (pro-proliferative: E2F1-3 and anti-proliferative: E2F4-8) and of their related genes cyclins and cyclin-dependent kinases (cdks) were evaluated in two HCC cell lines following a single BZB administration. mRNA levels of the epithelial-mesenchymal transition (EMT) genes were also measured in both cell lines after BZB treatment. The BZB concentration (40 nmol/L) used was chosen to stay well below the maximal amount/cm² recommended for in vivo application, and 2 d incubation was chosen as this time point has been found optimal to detect BZB effects in our previous studies. The HCC cell lines, HepG2 and JHH6, were chosen as they display different phenotypes, hepatocyte-like for HepG2 and undifferentiated for JHH6, thus representing an in vitro model of low and high aggressive forms of HCC, respectively. The mRNA levels of the target genes were measured by two-color microarray-based gene expression analysis, performed according to Agilent Technologies protocol and using an Agilent Scan B. For the E2F family members, mRNA levels were quantified by real-time reverse transcription polymerase chain reaction (RT-PCR). Using small interfering RNA's, the effects of E2F8 depletion on cell number was also evaluated.ResultsAfter BZB treatment, microarray analysis of the undifferentiated JHH6 revealed a significant decrease in the expression of the pro-proliferative E2F member E2F2. Quantitative RT-PCR data were in keeping with the microarray analysis, and showed a significant increase and decrease in E2F8 and E2F2 mRNA levels, respectively. In contrast, BZB treatment of the hepatocyte-like HCC cell line HepG2 had a significant impact on mRNA levels of 5 of the 8 E2F members. In particular, mRNA levels of the pro-proliferative E2F members E2F1, E2F2, and of the anti-proliferative member E2F8, decreased over 80%. Notably, a reduction in E2F8 expression in HepG2 and JHH6 cells following siRNA treatment had no impact on cell proliferation. As observed with JHH6, BZB treatment of HepG2 cells induced a significant increase in mRNA levels of an anti-proliferative E2F member, E2F6 in this case. As was observed with E2F's, more dramatic changes in mRNA levels of the E2F related genes cyclins and Cdks and EMT genes were observed after BZB treatment of HepG2 compared to JHH6.ConclusionThe differential expression of E2Fs and related genes induced by BZB in diverse HCC cell phenotypes contribute to bortezomib's mechanism of action in hepatocellular carcinoma.

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Comprehensive Analysis of E2F Family Members in Human Gastric Cancer.

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