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Death receptor 5 promotes tumor progression in gastric cancer.

ABSTRACT: Death receptor 5 (DR5) can inhibit malignant proliferation via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in many cancers. Here we examined the expression and sublocalization of DR5 in gastric cancer, as well as its effects on clinical prognosis and cellular processes. Our analysis included a cohort of 240 gastric cancer patients. Bioinformatic analysis showed a significant correlation between DR5 and DNA replication, tumor mutation burden (TMB), and tumor stemness. Unlike death receptor 4 (DR4TRAIL-R1), DR5 was expressed in the cytoplasm and nucleus, and was found to be positively correlated with lymphovascular invasion, lymph node metastasis, and TNM stage. Patients with positive DR5 had worse overall survival (OS) (P = 0.006). The multivariate Cox model showed that DR5 is an independent poor prognostic factor (hazard ratio = 1.693). Furthermore, knockdown of DR5 inhibited aggressive behaviors, including proliferation and metastasis in gastric cancer cells, and inhibited lung metastasis in vivo. In summary, nuclear localization of DR5 expression is a poor prognosis factor in gastric cancer and promotes growth, invasion, and metastasis of tumor cells in vitro and in vivo.

SUBMITTER: Chen J

PROVIDER: S-EPMC10699099 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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Death receptor 5 promotes tumor progression in gastric cancer.

Chen Junbing J Li Lin L Huangfu Longtao L Du Hong H Ji Xin X Xing Xiaofang X Ji Jiafu J

FEBS open bio 20231114 12

Death receptor 5 (DR5) can inhibit malignant proliferation via tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in many cancers. Here we examined the expression and sublocalization of DR5 in gastric cancer, as well as its effects on clinical prognosis and cellular processes. Our analysis included a cohort of 240 gastric cancer patients. Bioinformatic analysis showed a significant correlation between DR5 and DNA replication, tumor mutation burden (TMB), and tumor ...[more]

PMID: 37879960

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Project description:PurposeCollectin subfamily member 12, a transmembrane scavenger receptor C-type lectin, is aberrantly expressed in various cancers. However, its physiological role in gastric cancer remains somewhat unclear. This study aimed to investigate the Collectin subfamily member 12 expression pattern in human gastric cancer and its role in gastric cancer progression.MethodsThe Kaplan-Meier method was used for survival analysis. The univariate and multivariate Cox proportional hazards regression models were used to identify independent predictors for progression-free survival and overall survival. The effects of Collectin subfamily member 12 on gastric cancer cell proliferation, migration, invasion, and apoptosis were detected through the cell counting kit-8 assay, colony formation assay, wound healing assay, transwell assay, and flow cytometry analysis, respectively. Additionally, the correlation between Collectin subfamily member 12 expression and immune cell infiltration was analyzed through bioinformatics.ResultsCollectin subfamily member 12 was highly expressed in advanced gastric cancer (T3-T4, pathologic stage III-IV). High Collectin subfamily member 12 expression was correlated with a worse progression-free survival and overall survival in the gastric cancer patients. In vitro, cell line studies revealed that Collectin subfamily member 12 promoted gastric cancer cell proliferation, migration, and invasion and inhibited gastric cancer cell apoptosis. The bioinformatics analysis further demonstrated that the Collectin subfamily member 12 expression level positively correlated with infiltration of several immune cells, such as M2 macrophages, dendritic cells, neutrophils, and regulatory T cells, suggesting that Collectin subfamily member 12 may also play a role in suppressing tumor immune response in gastric cancer.ConclusionsCollectin subfamily member 12 was identified as a novel predictive marker and target for the clinical treatment of gastric cancer.

Project description:BackgroundThe Chromobox homolog 4 (CBX4) has been found to be overexpressed in multiple malignancies. However, the associations between CBX4 and gastric cancer (GC) have remained unclear. This study aimed to determine the biological roles of CBX4 in GC and identify effective therapeutic targets.MethodsThe 3-(4,5-dimethylthiazol-2-yl) (MTT) assays were used to screen CBX family members. Differential analysis was utilized to evaluate the CBX4 levels. Kaplan-Meier analysis was used to perform prognostic analysis. Western blotting assay, quantitative polymerase chain reaction (qPCR) assay and immunohistochemistry (IHC) were used to assess CBX4 expressions. Colony formation assay, Cell Counting Kit-8 (CCK-8) assay, and Transwell assay were used to assess progression features of cells. The tail vein injection model was utilized to determine the metastatic efficacy of GC cells. Tumor sphere formation assay was used to assess tumor stemness maintenance ability. Chromatin immunoprecipitation (ChIP)-qPCR assay was used to evaluate the associations between CBX4 and CDC20. A subcutaneous tumor model was used to assess the in vivo growth ability of GC.ResultsThe MTT assay revealed that only CBX4 inhibition could lead to notable restriction of GC growth, as compared to others. Differential analysis suggested that CBX4 was upregulated in tumor samples relative to normal tissues. Less favorable overall survival (OS) outcomes were noticed in GC patients with high CBX4 in comparison to those with low CBX4. High CBX4 could notably enhance cell proliferation capacity, migration ability, and in vivo metastatic efficacy. Gene set enrichment analysis (GSEA) indicated the relationships between CBX4 and GC stemness, and CBX4 overexpression could remarkably elevate self-renewal ability of GC cells. In addition, CBX4 could mainly promote CDC20 messenger RNA (mRNA) levels, and targeting CBX4 suppressed the relative CDC20 levels. The ChIP-qPCR assay further demonstrated that CBX4 coordinated with H3K4me3 to bind at the CDC20 promoter region. Additionally, CBX4 depended on CDC20 to drive GC growth. Lastly, downregulated CBX4 could notably inhibit the growth of GC in vivo.ConclusionsThis study highlights the oncogenic roles of CBX4 in GC. CBX4 activates CDC20 to maintain stemness features of GC, thereby creating therapeutic vulnerabilities in the treatment of GC.

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Death receptor 5 promotes tumor progression in gastric cancer.

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Death receptor 5 promotes tumor progression in gastric cancer.

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