Single-cell sequencing of multi-region resolves geospatial architecture and therapeutic target of endothelial cells in esophageal squamous cell carcinoma.
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ABSTRACT:
SUBMITTER: Dai J
PROVIDER: S-EPMC10660795 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
Publications
Single-cell sequencing of multi-region resolves geospatial architecture and therapeutic target of endothelial cells in esophageal squamous cell carcinoma.
Dai Jiacheng J Xi Xiaoxiang X Liu Zidong Z Wu Weicheng W Zhu Sibo S Zhang Xiaoyang X Huang Yuwei Y Meng Jiayue J Yuan Liyun L Suo Chen C Xue Jiangli J Yuan Ziyu Z Lv Ming M Ye Weimin W Jin Li L Zhang Guoqing G Chen Xingdong X
Clinical and translational medicine 20231101 11
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Project description:ObjectiveThe hyperactivated neddylation pathway plays an important role in tumorigenesis and is emerging as a promising anticancer target. We aimed to study whether NEDD8 (neural precursor cell expressed, developmentally down-regulated 8) might serve as a therapeutic target in esophageal squamous cell carcinoma (ESCC).MethodsThe clinical relevance of NEDD8 expression was evaluated by using The Cancer Genome Atlas (TCGA) database and tissue arrays. NEDD8-knockdown ESCC cells generated with the CRISPR/Cas9 system were used to explore the anticancer effects and mechanisms. Quantitative proteomic analysis was used to examine the variations in NEDD8 knockdown-induced biological pathways. The cell cycle and apoptosis were assessed with fluorescence activated cell sorting. A subcutaneous-transplantation mouse tumor model was established to investigate the anticancer potential of NEDD8 silencing in vivo.ResultsNEDD8 was upregulated at both the mRNA and protein expression levels in ESCC, and NEDD8 overexpression was associated with poorer overall patient survival (mRNA level: P = 0.028, protein level: P = 0.026, log-rank test). Downregulation of NEDD8 significantly suppressed tumor growth both in vitro and in vivo. Quantitative proteomic analysis revealed that downregulation of NEDD8 induced cell cycle arrest, DNA damage, and apoptosis in ESCC cells. Mechanistic studies demonstrated that NEDD8 knockdown led to the accumulation of cullin-RING E3 ubiquitin ligases (CRLs) substrates through inactivation of CRLs, thus suppressing the malignant phenotype by inducing cell cycle arrest and apoptosis in ESCC. Rescue experiments demonstrated that the induction of apoptosis after NEDD8 silencing was attenuated by DR5 knockdown.ConclusionsOur study elucidated the anti-ESCC effects and underlying mechanisms of NEDD8 knockdown, and validated NEDD8 as a potential target for ESCC therapy.
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Project description:ObjectiveEndothelial cell-specific molecule 1 (ESM1) has been implicated as an oncogene in several types of cancer. However, the potential role of ESM1 in esophageal carcinogenesis (ESCA)/esophageal squamous cell carcinoma (ESCC) is still unclear.MethodsThe expression, function, and survival data of ESM1 were observed using a bioinformatics approach. Subsequently, the expression level of ESM1 in surgical esophageal tumors and adjacent normal tissues was detected by qRT-PCR and immunofluorescence. We further revealed protein expression by immunohistochemistry (IHC), which is related to the prognosis of patients with ESCC using survival analysis. In vitro, knockdown of ESM1 in KYSE150 and KYSE510 cell lines, colony formation assays, wound healing assays, and Transwell assays were performed.ResultsESM1 is significantly elevated in 12 of 20 types of human cancer. ESM1 is highly expressed in tumor tissue compared with adjacent normal tissue and was identified as a hub gene in ESCA. Clinical outcome endpoints of overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS) curves showed that patients whose ESM1 expression was high had a lower clinical survival rate. The ESM1 high-expression group has a certain correlation with clinical stage and grade. The IHC of ESM1 further demonstrated that the higher the expression was, the worse the N classification and pTNM stage in patients with ESCC, which had a distinctly poorer overall 5-year survival rate. Univariate analysis showed that age, N classification, pTNM stage, and ESM1 expression were all prognostic factors, although multivariate Cox regression analysis showed that only pTNM stage was an independent prognostic factor. In vitro, silencing ESM1 suppressed the proliferation, migration, and invasion of KYSE150 and KYSE510 cells.ConclusionsESM1 is a hub gene in the initiation and progression of ESCA/ESCC that promotes the proliferation, migration, and invasion of esophageal cancer cells and may be a promising therapeutic target and prognostic indicator.
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Project description:PurposeTo establish a prognostic model of esophageal squamous cell carcinoma (ESCC) patients based on tenascin-C (TNC) expression level and clinicopathological characteristics, and to explore the therapeutic potential of TNC inhibition.MethodsThe expression of TNC was detected using immunohistochemistry (IHC) in 326 ESCC specimens and 50 normal esophageal tissues. Prognostic factors were determined by Cox regression analyses and were incorporated to establish the nomogram. The effects of TNC knockdown on ESCC cells were assessed in vitro and in vivo. Transcriptome sequencing (RNA-seq) and gene set enrichment analysis (GSEA) were performed to reveal signaling pathways regulated by TNC knockdown. The therapeutic significance of TNC knockdown combined with small-molecule inhibitors on cell proliferation was examined.ResultsTNC protein was highly expressed in 48.77 % of ESCC tissues compared to only 2 % in normal esophageal epithelia (p < 0.001). The established nomogram model, based on TNC expression, pT stage, and lymph node metastasis, showed good performance on prognosis evaluation. More importantly, the reduction of TNC expression inhibited tumor cell proliferation and xenograft growth, and mainly down-regulated signaling pathways involved in tumor growth, hypoxia signaling transduction, metabolism, infection, etc. Knockdown of TNC enhanced the inhibitory effect of inhibitors targeting ErbB, PI3K-Akt, Ras and MAPK signaling pathways.ConclusionThe established nomogram may be a promising model for survival prediction in ESCC. Reducing TNC expression enhanced the sensitivity of ESCC cells to inhibitors of Epidermal Growth Factor Receptor (EGFR) and downstream signaling pathways, providing a novel combination therapy strategy.
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Project description:Rationale: Whole-genome sequencing has identified many amplified genes in esophageal squamous-cell carcinoma (ESCC). This study investigated the role and clinical relevance of these genes in ESCC. Methods: We collected ESCC and non-tumor esophageal tissues from 225 individuals who underwent surgery. Clinical data were collected and survival time was measured from the date of diagnosis to the date of last follow-up or death. Patient survival was compared with immunohistochemical staining score using Kaplan-Meier methods and hazard ratios were calculated by Cox models. Cells with gene overexpression and knockout were analyzed in proliferation, migration and invasion assays. Cells were also analyzed for levels of intracellular lactate, NADPH, ATP and mRNA and protein expression patterns. Protein levels in cell line and tissue samples were measured by immunoblotting or immunohistochemistry. ESCC cell were grown as xenograft tumors in nude mice. Primary ESCC in genetically engineered mice and patient-derived xenograft mouse models were established for test of therapeutic effects. Results: We show that TP53-induced glycolysis and apoptosis regulator (TIGAR) is a major player in ESCC progression and chemoresistance. TIGAR reprograms glucose metabolism from glycolysis to the glutamine pathway through AMP-activated kinase, and its overexpression is correlated with poor disease outcomes. Tigar knockout mice have reduced ESCC tumor burden and growth rates. Treatment of TIGAR-overexpressing ESCC cell xenografts and patient-derived tumor xenografts in mice with combination of glutaminase inhibitor and chemotherapeutic agents achieves significant more efficacy than chemotherapy alone. Conclusion: These findings shed light on an important role of TIGAR in ESCC and might provide evidence for targeted treatment of TIGAR-overexpressing ESCC.
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Project description:Esophageal squamous-cell carcinoma (ESCC) is one of the most common malignancies in Asia. Currently, surgical resection of early-stage tumor is the best available treatment. However, most patients present late when surgery is not an option. Data suggest that chemotherapy regimens are inadequate for clinical management of advanced cancer. Targeted therapy has emerged as one of the most promising approaches to treat several malignancies. A prerequisite for developing targeted therapy is prior knowledge of proteins and pathways that drive proliferation in malignancies. We carried out phosphotyrosine profiling across four different ESCC cell lines and compared it to non-neoplastic Het-1A cell line to identify activated tyrosine kinase signaling pathways in ESCC. A total of 278 unique phosphopeptides were identified across these cell lines. This included several tyrosine kinases and their substrates that were hyperphosphorylated in ESCC. Ephrin receptor A2 (EPHA2), a receptor tyrosine kinase, was hyperphosphorylated in all the ESCC cell lines used in the study. EPHA2 is reported to be oncogenic in several cancers and is also known to promote metastasis. Immunohistochemistry-based studies have revealed EPHA2 is overexpressed in nearly 50% of ESCC. We demonstrated EPHA2 as a potential therapeutic target in ESCC by carrying out siRNA-based knockdown studies. Knockdown of EPHA2 in ESCC cell line TE8 resulted in significant decrease in cell proliferation and invasion, suggesting it is a promising therapeutic target in ESCC that warrants further evaluation.
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Project description:Cyclooxygenase-2 (COX-2) is known to promote the carcinogenesis of esophageal squamous cell carcinoma (ESCC). There are no reports on whether microRNAs (miRNAs) regulate COX-2 expression in ESCC. This study investigated the effect of miR-101 on ESCC through modulating COX-2 expression in ESCC.Real-time quantitative reverse transcription-polymerase chain reaction (RT-PCR) was used to quantify miR-101 expression in ESCC clinical tissues and cell lines. The effects of miR-101 on ESCC progression were evaluated by cell counting kit-8 (CCK8), transwell migration and invasion assays, as well as by flow cytometry. The COX-2 and PEG2 levels were determined by western blot and enzyme-linked immunosorbent assays (ELISA). The luciferase reporter assay was used to verify COX-2 as a direct target of miR-101. The anti-tumor activity of miR-101 in vivo was investigated in a xenograft nude mouse model of ESCC.Downregulation of miR-101 was confirmed through comparison of 30 pairs of ESCC tumor and adjacent normal tissues (P < 0.001), as well as in 11 ESCC cell lines and a human immortalized esophageal cell line (P < 0.001). Transfection of miR-101 in ESCC cell lines significantly suppressed cell proliferation, migration, and invasion (all P < 0.001). The antitumor effect of miR-101 was verified in a xenograft model. Furthermore, COX-2 was shown to be a target of miR-101.Overexpression of miR-101 in ESCC inhibits proliferation and metastasis. Therefore, the miR-101/COX-2 pathway might be a therapeutic target in ESCC.
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Project description:Purpose: Ubiquitin-like with plant homeodomain and ring-finger domains 1 (UHRF1) plays an essential role in DNA methylation, and the overexpression of UHRF1 is associated with poor prognosis in various cancers. Esophageal squamous cell carcinoma (ESCC) accounts for approximately 90% of esophageal cancer cases in China, but the five-year survival rate for patients is less than 10% due to limited clinical approaches for early diagnosis and treatment. The present research aimed to investigate the expression of UHRF1 in ESCC and its biological role in ESCC development. Methods: UHRF1 expression in ESCC and normal esophageal tissues was examined using immunohistochemical staining, followed by analysis of the correlation between UHRF1 expression and clinical features. In addition, the effects of lentivirus-mediated RNA interference of UHRF1 on global DNA methylation, cell proliferation, cell cycle progression and apoptosis and were investigated in ESCC cells. Results: UHRF1 was overexpressed in ESCC tissues and was an independent prognostic factor for ESCC patients. In ESCC cells, knockdown of UHRF1 caused global DNA hypomethylation, inhibited cell proliferation and induced apoptosis. Furthermore, UHRF1 depletion induced cell cycle arrest at the G2/M phase, accompanied by activation of Wee1 and DNA damage response pathway. Conclusions: Our findings identify UHRF1 as a promising prognostic marker for ESCC and suggest that UHRF1 may be a potential therapy target for ESCC patients with elevated UHRF1 expression.
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