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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:To evaluate the effects of the proteasome inhibitor bortezomib (BZB) on E2Fs and related genes in hepatocellular carcinoma (HCC) cells.The 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.After 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.The 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.

Project description:The solute carrier 30 (SLC30) family genes play a fundamental role in various cancers. However, the diverse expression patterns, prognostic value, and potential mechanism of SLC30A family genes in gastric cancer (GC) remain unknown. Herein, we analyzed the expression and survival data of SLC30A family genes in GC patients using multiple bioinformatic approaches. Expression data of SLC30A family genes for GC patients were extracted from the Cancer Genome Atlas (TCGA) and genetic alteration frequency assessed by using cBioportal database. And validated the expression of SLC30A family genes in GC tissues and corresponding normal tissues. The prognostic value of SLC30A family genes in gastric cancer patients were explored using Kaplan-Meier plotter database. Functional enrichment analysis performed using DAVID database and clusterProfiler package. And ssGSEA algorithm was performed to explore the relationship between the SLC30A family genes and the infiltration of immune cells. We found that the median expression levels of SLC30A1-3, 5-7, and 9 were significantly upregulated in gastric cancer tissues compared to non-cancerous tissues, while SLC30A4 was downregulated. Meanwhile, SLC30A1-7, and 9 were significantly correlated with advanced tumor stage and nodal metastasis status, SLC30A5-7, and 9-10 were significantly related to the Helicobacter pylori infection status of GC patients. High expression of five genes (SLC30A1, 5-7, and 9) was significantly correlated with better overall survival (OS), first progression survival (FPS), and post progression survival (PPS). Conversely, upregulated SLC30A2-4, 8, and 10 expression was markedly associated with poor OS, FP and PPS. And SLC30A family genes were closely associated with the infiltration of immune cells. The present study implied that SLC30A5 and 7 may be potential biomarkers for predicting prognosis in GC patients, SLC30A2 and 3 play an oncogenic role in GC patients and could provide a new strategy for GC patients treatment.

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Comprehensive Analysis of E2F Family Members in Human Gastric Cancer.

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