GRB7 Plays a Vital Role in Promoting the Progression and Mediating Immune Evasion of Ovarian Cancer
<p>The expression of GRB7. (<b>A</b>,<b>B</b>) GRB7 mRNA levels in pan-cancer (<b>A</b>), OC (<b>B</b>), and the corresponding normal tissues in TCGA and GTEx databases. (<b>C</b>–<b>E</b>) GRB7’s expression in OC and normal tissues in GEO databases, GSE6008 (<b>C</b>), GSE36668 (<b>D</b>), and GSE66957 (<b>E</b>). (<b>F</b>) GRB7 protein levels in OC and paired adjacent normal tissues from cProCite database. (<b>G</b>) Representative results of immunochemically stained GRB7 proteins in OC and normal ovarian tissues from Human Protein Atlas. * <span class="html-italic">p</span> < 0.05; *** <span class="html-italic">p</span> < 0.001 by unpaired Student’s <span class="html-italic">t</span> test (<b>A</b>–<b>F</b>). ns, not significant.</p> "> Figure 2
<p>The prognosis and diagnosis value of GRB7 in OC. (<b>A</b>–<b>D</b>) OS, DSS, DFI, and PFI curves of lowly and highly expressed GRB7 in OC. (<b>E</b>) Univariate and multivariate regression analyses of GRB7 and clinicopathologic factors with OS in OC patients from TCGA. (<b>F</b>) A nomogram to predict OS probability at 1-year, 2-year, and 3-year overall survival probabilities for OC. * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001 by unpaired Student’s t test (E, F). # Events represents the number of death cases.</p> "> Figure 3
<p>Gene expression and enrichment of GRB7-associated gene in OC from TCGA. (<b>A</b>) Heatmap of top 20 genes positively correlated with GRB7 and top 20 negatively correlated genes in OC. (<b>B</b>) KEGG enrichment results of all 225 different expressed genes. (<b>C</b>) Biological processes, cellular components, and molecular functions from GO enrichment results. (<b>D</b>) Chord diagrams of biological processes.</p> "> Figure 4
<p>The immune infiltration and association with immunotherapy response of GRB7 in OC. (<b>A</b>) Immune cell enrichment in low and high expression levels of GRB7 in OC from CIBERSORT. (<b>B</b>) GRB7’s expression levels in responders and non-responders of ICB in syngeneic mouse models. (<b>C</b>) Protein–protein interaction signature of GRB7 from string database. (<b>D</b>,<b>E</b>) The GRB7 signature expression level in responders and non-responders of ICB-treated clinical cohorts, PD1 + CTLA4 in melanoma (<b>D</b>), and PDL1 in metastatic urothelial cancer (<b>E</b>). (<b>F</b>) GRB7 knockout in cancer cells cocultured with T cells from several CRISPR-Cas9 screens. Box plots indicate median (middle line), 25th and 75th percentile (box), and 5th and 95th percentile (whiskers) (<b>A</b>,<b>B</b>,<b>D</b>,<b>E</b>), and each dot in the scatter represents an individual patient sample (<b>D</b>,<b>E</b>). * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001 by unpaired Student’s <span class="html-italic">t</span> test (<b>A</b>,<b>B</b>,<b>D</b>,<b>E</b>). ns, not significant.</p> "> Figure 5
<p>GRB7’s expression among different cell types and datasets. The cohorts highlighted in red are the ovarian cancer single-cell datasets.</p> "> Figure 6
<p>Knockout GRB7 inhibits the proliferation of OVCAR3. (<b>A</b>) Western blot analysis of GRB7 knockout efficiency. (<b>B</b>) Colony formation capacity of GRB7 knockout and control. (<b>C</b>) CCK-8 assay of GRB7 knockout and control. Data are represented as mean ± standard deviation (SD) (<b>A</b>–<b>C</b>). The Shapiro–Wilk test confirmed normality, and Brown–Forsythe test confirmed homogeneity of variance (<b>B</b>,<b>C</b>). * <span class="html-italic">p</span> < 0.05; ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001 by one-way ANOVA (<b>B</b>) and two-way ANOVA (<b>C</b>). Data are representative of three independent experiments (<b>B</b>,<b>C</b>).</p> "> Figure 7
<p>GRB7 knockout in OVCAR3 inhibits cell migration and sensitizes killing effect of CD8+ T cells. (<b>A</b>) GRB7 knockout in OVCAR3 reduces migrating cell numbers in transwell assay. (<b>B</b>) GRB7 knockout in OVCAR3 slows wound healings. (<b>C</b>) The representative FACS results and summary of the log2 fold change in the ratio of GRB7 KO cells over the control after adding CD8+ T cells. The pseudocolor in the figure represents the variation in cell density. Colors range from red to blue, indicating a gradual decrease in cell density from high to low. Data are represented as mean ± SD (<b>A</b>–<b>C</b>). The Shapiro–Wilk test confirmed normality, and Brown–Forsythe test confirmed homogeneity of variance (<b>A</b>–<b>C</b>). ** <span class="html-italic">p</span> < 0.01; *** <span class="html-italic">p</span> < 0.001 by one-way ANOVA (<b>A</b>–<b>C</b>). Data are representative of three independent experiments (<b>A</b>–<b>C</b>).</p> ">
Abstract
:1. Introduction
2. Results
2.1. GRB7’s Expression Is Upregulated in Ovarian Cancer Tissue
2.2. GRB7’s Expression Is Independently Associated with a Poorer Outcome and Is Valuable for Predicting OS in OC Patients
2.3. Network Establishment for GRB7-Correlated Genes in OC
2.4. GRB7’s Expression Correlates with Immune Infiltration and Immunotherapy Response and Has Potential to Be a Therapeutic Target
2.5. GRB7 Knockout Inhibits OC Cell Proliferation and Migration
2.6. Enhanced Susceptibility of OC Cells to T Cell-Mediated Cytotoxicity Post-GRB7 Knockout
3. Discussion
4. Materials and Methods
4.1. Expression of GRB7 and Clinicopathological Character Analysis
4.2. Correlation Analysis of GRB7 and Prognosis
4.3. Analyses of Univariate and Multivariate Cox Regression
4.4. Correlation of Related Genes and Gene Set Enrichment Analysis
4.5. Immune Cell Infiltration and Association with Immunotherapy
4.6. GRB7’s Expression Level in Single Cells of Tumor Tissue
4.7. Cell Culture
4.8. Cell Proliferation
4.9. Cell Migration
4.10. In Vitro Cancer-Killing Assay by Antigen-Specific T Cells
4.11. Statistical Analyses
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Wen, L.; Hu, W.; Hou, S.; Luo, C.; Jin, Y.; Zeng, Z.; Zhang, Z.; Meng, Y. GRB7 Plays a Vital Role in Promoting the Progression and Mediating Immune Evasion of Ovarian Cancer. Pharmaceuticals 2024, 17, 1043. https://doi.org/10.3390/ph17081043
Wen L, Hu W, Hou S, Luo C, Jin Y, Zeng Z, Zhang Z, Meng Y. GRB7 Plays a Vital Role in Promoting the Progression and Mediating Immune Evasion of Ovarian Cancer. Pharmaceuticals. 2024; 17(8):1043. https://doi.org/10.3390/ph17081043
Chicago/Turabian StyleWen, Liang, Wei Hu, Sen Hou, Ce Luo, Yiteng Jin, Zexian Zeng, Zhe Zhang, and Yuanguang Meng. 2024. "GRB7 Plays a Vital Role in Promoting the Progression and Mediating Immune Evasion of Ovarian Cancer" Pharmaceuticals 17, no. 8: 1043. https://doi.org/10.3390/ph17081043