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EphB2 represents an independent prognostic marker in patients with gastric cancer and promotes tumour cell aggressiveness.

ABSTRACT: Dysregulated expression of ephrin type-B receptor 2 (EphB2) has been linked with the development and progression of solid tumours. In the current study, we attempted to investigate the clinical relevance in GC and the effect of EphB2 expression on gastric cancer (GC) cells. EphB2 protein levels in GC and benign gastric tissues were determined using immunohistochemistry. EphB2 transcript expression in a GC cohort with GC tissue samples (n=171) and paired adjacent normal gastric tissues (n=97) was determined using qPCR. The EphB2 expression was over-activated using a CRISPR activator for the investigation of its cellular function. The expression levels of the EphB2 protein in the tumour tissues of tissue arrays were higher than the benign non-cancerous gastric tissues (P<0.05). EphB2 mRNA expression in GC tissues was also significantly elevated when compared with adjacent non-cancerous tissues (P<0.01). EphB2 activation promoted the migration and invasion abilities of the GC cell lines (P<0.01, respectively). In contrast, EphB2 activation significantly decreased the adhesion in GC cells (P<0.0001, respectively). The enrichment analysis of the correlated genes in a GC cohort indicates that EphB2 may function through mediating the cytokine-cytokine interaction, JAK-STAT and TP53 signaling pathways. In conclusion, EphB2 represents as a novel independent prognostic marker in GC. And activation of the EphB2 gene expression elevated the levels of migration and invasion, but suppressed adhesion of GC cells, indicating that EphB2 may act as a tumour promotor in GC. Our findings thus provide fundamental evidence for the consideration of the therapeutic potential of targeting EphB2 in GC.

SUBMITTER: Yin J

PROVIDER: S-EPMC7086246 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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EphB2 represents an independent prognostic marker in patients with gastric cancer and promotes tumour cell aggressiveness.

Yin Jie J Li Zhilei Z Ye Lin L Birkin Emily E Li Liting L Xu Rui R Chen Guangyong G Ji Jiafu J Zhang Zhongtao Z Jiang Wen G WG Cui Yuxin Y

Journal of Cancer 20200221 10

Dysregulated expression of ephrin type-B receptor 2 (EphB2) has been linked with the development and progression of solid tumours. In the current study, we attempted to investigate the clinical relevance in GC and the effect of EphB2 expression on gastric cancer (GC) cells. EphB2 protein levels in GC and benign gastric tissues were determined using immunohistochemistry. EphB2 transcript expression in a GC cohort with GC tissue samples (n=171) and paired adjacent normal gastric tissues (n=97) was ...[more]

PMID: 32226496

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Project description:BackgroundApproaches based on expression signatures of prostate cancer (PCa) have been proposed to predict patient outcomes and response to treatments. The transcription factor NF-Y participates to the progression from benign epithelium to both localized and metastatic PCa and is associated with aggressive transcriptional profile. The gene encoding for NF-YA, the DNA-binding subunit of NF-Y, produces two alternatively spliced transcripts, NF-YAs and NF-YAl. Bioinformatic analyses pointed at NF-YA splicing as a key transcriptional signature to discriminate between different tumor molecular subtypes. In this study, we aimed to determine the pathophysiological role of NF-YA splice variants in PCa and their association with aggressive subtypes.MethodsData on the expression of NF-YA isoforms were extracted from the TCGA (The Cancer Genome Atlas) database of tumor prostate tissues and validated in prostate cell lines. Lentiviral transduction and CRISPR-Cas9 technology allowed the modulation of the expression of NF-YA splice variants in PCa cells. We characterized 3D cell cultures through in vitro assays and RNA-seq profilings. We used the rank-rank hypergeometric overlap approach to identify concordant/discordant gene expression signatures of NF-YAs/NF-YAl-overexpressing cells and human PCa patients. We performed in vivo studies in SHO-SCID mice to determine pathological and molecular phenotypes of NF-YAs/NF-YAl xenograft tumors.ResultsNF-YA depletion affects the tumorigenic potential of PCa cells in vitro and in vivo. Elevated NF-YAs levels are associated to aggressive PCa specimens, defined by Gleason Score and TNM classification. NF-YAl overexpression increases cell motility, while NF-YAs enhances cell proliferation in PCa 3D spheroids and xenograft tumors. The transcriptome of NF-YAs-spheroids has an extensive overlap with localized and metastatic human PCa signatures. According to PCa PAM50 classification, NF-YAs transcript levels are higher in LumB, characterized by poor prognosis compared to LumA and basal subtypes. A significant decrease in NF-YAs/NF-YAl ratio distinguishes PCa circulating tumor cells from cancer cells in metastatic sites, consistently with pro-migratory function of NF-YAl. Stratification of patients based on NF-YAs expression is predictive of clinical outcome.ConclusionsAltogether, our results indicate that the modulation of NF-YA isoforms affects prostate pathophysiological processes and contributes to cancer-relevant phenotype, in vitro and in vivo. Evaluation of NF-YA splicing may represent a new molecular strategy for risk assessment of PCa patients.

Project description:Background: Approaches based on expression signatures of prostate cancer (PCa) have been proposed to predict patients’ outcomes and response to treatments. The transcription factor NF-Y participates to the progression from benign epithelium to both localized and metastatic PCa and is associated with aggressive transcriptional profile. The gene encoding for NF-YA, the DNA-binding subunit of NF-Y, produces two alternatively spliced transcripts, NF-YAs and NF-YAl. Bioinformatic analyses pointed at NF-YA splicing as a key transcriptional signature to discriminate between different tumor molecular subtypes. In this study, we aimed to determine the pathophysiological role of NF-YA splice variants in PCa and their association with aggressive PCa subtypes. Methods: Data on the expression of NF-YA isoforms were extracted from the TCGA (The Cancer Genome Atlas) database of tumor prostate tissues and validated in prostate cell lines. Through lentiviral transduction and CRISPR-Cas9 technology, we modulated the expression of NF-YA splice variants in prostate cancer cells. We investigated cellular and molecular effects on cancer programs through 2D/3D in vitro assays and RNA-seq profilings. The rank-rank hypergeometric overlap approach (RRHO) was used to identify concordant/discordant overlap between gene expression signatures of NF-YAs/NF-YAl cells and human PCa patients. We performed in vivo studies in SHO-SCID mice to determine pathological and molecular phenotypes of NF-YAs/NF-YAl xenograft tumors. Results: NF-YA depletion affects the tumorigenic potential of prostate cancer cells in vitro and in vivo. Elevated NF-YAs levels are associated to aggressive prostate cancer specimens, defined by Gleason Score and TNM classification. NF-YAl overexpression in prostate cancer cells increases cell motility, while NF-YAs enhances both cell proliferation and invasive properties in 3D cultured spheroids and xenograft tumors. NF-YAs-transcriptome of multi-cellular spheroids has an extensive overlap with both localized and metastatic human PCa signatures. The ratio between NF-YAs and NF-YAl transcripts is higher in LumB PAM50 subtype, characterized by poor prognosis, and stratification of patients based on NF-YAs expression is predictive of clinical outcome. Conclusions: Altogether, our results indicate that the modulation of NF-YA isoforms affects prostate pathophysiological processes and contributes to cancer-relevant phenotype, in vitro and in vivo. Evaluation of NF-YA splicing may represent a new molecular strategy for risk assessment of PCa patients.

Dataset Information

EphB2 represents an independent prognostic marker in patients with gastric cancer and promotes tumour cell aggressiveness.

Publications

EphB2 represents an independent prognostic marker in patients with gastric cancer and promotes tumour cell aggressiveness.

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