Dataset Information

Potential Role of Targeting KDR and Proteasome Inhibitors in the Therapy of Esophageal Squamous Cell Carcinoma.

ABSTRACT: Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancer types in China. In recent years, progress has been made in various types of cancer genomics including ESCC. However, the clinical significance of genomic variation of ESCC remains poorly defined. In the present study, genomic sequencing data from 469 ESCC cases were analyzed and potential therapeutic targets in the Druggable Genome Interaction Database (DGIdb) were screened. A series of potential therapeutic target genes and pathways were identified, of which treatment of ESCC with bortezomib (a specific inhibitor targeting proteasome) potently inhibited the proliferation of 5 ESCC cell lines and administration of bortezomib led to significant tumor xenograft regression in SCID mice. It was also identified that kinase insert domain receptor (KDR), which had drug recommendations from all 6 sources integrated by the DGldb and harbored significant amplification in ESCC, might be a downstream target of zinc finger protein 750 (ZNF750). ZNF750 acts as a transcription factor and has been demonstrated to harbor frequently inactivating mutations in ESCC by previous independent studies. In the present study, KDR was upregulated upon ZNF750 knockdown and the rescue of ZNF750 also led to marked restoration of KDR. KDR knockdown in stable ZNF750-knockdown KYSE150 and KYSE140 ESCC cells significantly attenuated the promotion of cell growth, colony formation, invasion and migration induced by ZNF750 knockdown. Further experiments found that apatinib treatment, a potent inhibitor of KDR, resulted in profound inhibition of cell proliferation and invasion. Collectively, the present study provided insight for genomic alterations as potential therapeutic targets in ESCC and supported the possibility of a therapeutic strategy targeting the proteasome in ESCC. The present results also suggested that targeting KDR may be an effective way to treat ESCC, not only in KDR variant cases, but also in individuals with ZNF750 mutations and deletions.

SUBMITTER: Zhang L

PROVIDER: S-EPMC7493273 | biostudies-literature | 2020 Jan-Dec

REPOSITORIES: biostudies-literature

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Potential Role of Targeting KDR and Proteasome Inhibitors in the Therapy of Esophageal Squamous Cell Carcinoma.

Zhang Ling L Niu Xia X Bi Yanghui Y Cui Heyang H Li Hongyi H Cheng Xiaolong X

Technology in cancer research & treatment 20200101

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancer types in China. In recent years, progress has been made in various types of cancer genomics including ESCC. However, the clinical significance of genomic variation of ESCC remains poorly defined. In the present study, genomic sequencing data from 469 ESCC cases were analyzed and potential therapeutic targets in the Druggable Genome Interaction Database (DGIdb) were screened. A series of potential therapeutic target ge ...[more]

PMID: 32924793

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Project description:BackgroundChimeric antigen receptor NK (CAR-NK) cell therapy is one of the most promising immunotherapies. Although it has shown a significant therapeutic effect in hematologic malignancies, few successes have been obtained in solid tumors including esophageal squamous cell carcinoma (ESCC). The major reasons are lack of specific cell surface antigens and complex tumor microenvironment. Here we identify CD22, a well-known tumor surface marker in hematologic malignancies, is expressed in ESCC, possibly serving as a potential target of CAR-NK cell therapy.MethodsThe expression of 13 tumor cell surface antigens used clinically was analyzed in patients from The Cancer Genome Atlas (TCGA) database. Also, mRNA expression were detected in 2 ESCC cell lines and 2 patients samples by qCPR. Then according to Venn diagram, CD22 was selected for further investigation. Following this, the expression of CD22 by immunofluorescence (IF) in ESCC cell lines and by immunohistochemistry (IHC) in 87 cases of human ESCC samples was detected respectively. On the basis of H-score results, the correlation between CD22 expression and clinical parameters was analyzed. As a proof, the efficacy of CD22-targeted CAR-NK cells against ESCC cell lines was performed by a real-time cell analyzer (RTCA) platform.ResultsKYSE-140 and KYSE-150 cell lines displayed surface expression of CD22. IHC showed an 80.46% (70/87) positive rate in ESCC patient samples. Among these, cell membranous expression of CD22 was observed in 27.59% (24/87) patient samples. Through chi-square test, expression of CD22 in ESCC was associated with lymph node metastasis while it was no related to the depth of tumor invasion and clinical stage. Engineered CD22-targeted CAR-NK cells exhibited inhibitory growth capability against ESCC cell lines (p < 0.0001).ConclusionsCD22 is a potential tumor surface antigen capable of being targeted by CAR-NK cells in ESCC. And potential therapeutics for ESCC may be developed based on immune cells expressing anti-CD22 CAR. The study also indicates that CD22 CAR-NK cells could be used in other cancers and more in vivo experiments are needed.

Project description:BackgroundThe incidence of esophageal squamous cell carcinoma in China ranks first in the world. The early diagnosis technology is underdeveloped, and the prognosis is poor, which seriously threatens the quality of life of the Chinese people. Epidemiological findings are related to factors such as diet, living habits, and age. The specific mechanism is not clear yet. Metabolomics is a kind of omics that simultaneously and quantitatively analyzes the comprehensive profile of metabolites in living systems. It has unique advantages in the study of the diagnosis and pathogenesis of tumor-related diseases, especially in the search for biomarkers. Therefore, it is desirable to perform metabolic profiling analysis of cancer tissues through metabolomics to find potential biomarkers for the diagnosis and treatment of esophageal squamous cell carcinoma.MethodsHPLC-TOF-MS/MS technology and Illumina Hiseq Xten Sequencing was used for the analysis of 210 pairs of matched esophageal squamous cell carcinoma tissues and normal tissues in Zhenjiang City, Jiangsu Province, a high-incidence area of esophageal cancer in China. Bioinformatics analysis was also performed.ResultsThrough metabolomic and transcriptomic analysis, this study found that a total of 269 differential metabolites were obtained in esophageal squamous cell carcinoma and normal tissues, and 48 differential metabolic pathways were obtained through KEGG enrichment analysis. After further screening and identification, 12 metabolites with potential biomarkers to differentiate esophageal squamous cell carcinoma from normal tissues were obtained.ConclusionsFrom the metabolomic data, 4 unknown compounds were found to be abnormally expressed in esophageal squamous cell carcinoma for the first time, such as 9,10-epoxy-12,15-octadecadienoate; 3 metabolites were found in multiple abnormal expression in another tumor, but upregulation or downregulation was found for the first time in esophageal cancer, such as oleoyl glycine; at the same time, it was further confirmed that five metabolites were abnormally expressed in esophageal squamous cell carcinoma, which was similar to the results of other studies, such as PE.

Dataset Information

Potential Role of Targeting KDR and Proteasome Inhibitors in the Therapy of Esophageal Squamous Cell Carcinoma.

Publications

Potential Role of Targeting KDR and Proteasome Inhibitors in the Therapy of Esophageal Squamous Cell Carcinoma.

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