Dataset Information

Aspartate β-Hydroxylase Serves as a Prognostic Biomarker for Neoadjuvant Chemotherapy in Gastric Cancer.

ABSTRACT: Neoadjuvant chemotherapy (NACT) has been established as being an effective treatment for advanced gastric cancer (GC), while the predictive biomarker of NACT efficacy remains under investigation. Aspartate β-hydroxylase (ASPH) represents an attractive target which is a highly conserved transmembrane enzyme overexpressed in human GC, and participates in the malignant transformation by promoting tumor cell motility. Here, we evaluated the expression of ASPH by immunohistochemistry in 350 GC tissues (including samples for NACT) and found that ASPH expression was higher in patients undergoing NACT compared with patients without NACT pre-operation. The OS and PFS time of ASPH-intensely positive patients was significantly shorter than that of the negative patients in the NACT group, while the difference was not significant in patients without NACT. We showed that ASPH knockout enhanced the inhibitory effects of chemotherapeutic drugs on the cell proliferation, migration, and invasion in vitro and suppressed tumor progression in vivo. Co-immunoprecipitation revealed that ASPH might interact with LAPTM4B to perform chemotherapeutic drug resistance. Our results suggested that ASPH might serve as a candidate biomarker to predict prognosis and a novel therapeutic target for gastric cancer patients treated with neoadjuvant chemotherapy.

SUBMITTER: Gan X

PROVIDER: S-EPMC10053938 | biostudies-literature | 2023 Mar

REPOSITORIES: biostudies-literature

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Aspartate β-Hydroxylase Serves as a Prognostic Biomarker for Neoadjuvant Chemotherapy in Gastric Cancer.

Gan Xuejun X Li Shen S Wang Yiding Y Du Hong H Hu Ying Y Xing Xiaofang X Cheng Xiaojing X Yan Yan Y Li Ziyu Z

International journal of molecular sciences 20230313 6

Neoadjuvant chemotherapy (NACT) has been established as being an effective treatment for advanced gastric cancer (GC), while the predictive biomarker of NACT efficacy remains under investigation. Aspartate β-hydroxylase (ASPH) represents an attractive target which is a highly conserved transmembrane enzyme overexpressed in <i>human</i> GC, and participates in the malignant transformation by promoting tumor cell motility. Here, we evaluated the expression of ASPH by immunohistochemistry in 350 GC ...[more]

PMID: 36982561

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Project description:AimsGallbladder cancer is characterized by a dismal prognosis, with a limited number of biological markers currently identified for the carcinogenesis, progression and prognosis of gallbladder cancers (GBCs). The discovery of efficacious biomarkers is crucial for enhancing the prognosis of gallbladder cancer.MethodsAnalysis of RNAseq datasets from gallbladder cancer allowed the identification of differential genes between gallbladder cancer and adjacent tissues. Subsequent application of Mendelian randomization extracted target gene known to promote gallbladder cancer from these differentially expressed genes. Immunohistochemistry was then conducted to evaluate the expression of these target gene in a cohort of 215 patients with gallbladder cancer, utilizing follow-up information to determine their prognostic value. Moreover, single-cell sequencing data of gallbladder cancer elucidated the role of target genes within the immune microenvironment of this cancer type. The Genomics of Therapeutics Response Portal (CTRP) database enabled the assessment of the impact of target genes on the IC50 of chemotherapy drugs. Lastly, network pharmacology and analytical methodologies were employed to investigate the effects of traditional Chinese medicine active ingredients targeting these specific genes.ResultsASPH expression is notably elevated in gallbladder cancer tissues, correlating with an unfavorable prognosis for patients afflicted with this disease. Results from Mendelian randomization studies suggest that heightened ASPH levels play a significant role in the development of gallbladder polyps and stones, which are established clinical risk factors in gallbladder cancer. Analysis of clinical samples demonstrates a positive association between ASPH expression and indicators of poor differentiation, increased tumor size, advanced TNM stage, lymph node metastasis, and invasion. The single-cell immune microenvironment reveals that ASPH not only enhances the expression of immune checkpoints, namely PDL1 and PVR, in the gallbladder cancer epithelium, resulting in immune evasion, but also triggers epithelial-mesenchymal transition and migration, promoting metastasis. Furthermore, ASPH contributes to heightened tumor drug metabolism, hence raising the IC50 values for gemcitabine and paclitaxel. Utilizing network pharmacology and molecular docking techniques, this study pinpointed six bioactive compounds derived from traditional Chinese medicine with a targeted effect on the ASPH protein, comprising Sebacic acid, Suberic acid, Azelaic acid, Dimelic acid, Succinic acid, and D-Asparaginsaeure.ConclusionsASPH plays a role in promoting the development of gallbladder cancer and resistance to chemotherapeutic agents, rendering it a promising target for therapeutic interventions. Active therapeutic compounds targeted on ASPH can be identified among the active ingredients present in traditional Chinese medicine.

Project description:Gastric carcinoma (GC) refers to a common digestive system disease that exhibits a very high incidence. MicroRNA hsa-mir-3923 belongs to a type of miRNA, of which the function has been merely investigated in breast, pancreatic cancers and pre-neoplasic stages of gastric cancer. It has not been studied or reported in gastric carcinoma, so the relationship between gastric hsa-mir-3923 expression and the clinics feature and pathology of GC cases was examined. This study employed data mining for analyzing gastric carcinoma data in The Cancer Genome Atlas database. A Chi squared test was performed for assessing the relations of hsa-mir-3923 expression with clinics-related and pathology-regulated variables. This study conducted the assessment of the role of hsa-mir-3923 in prognostic process using Kaplan-Meier curves, Receiver operating characteristic (ROC) analysis and proportional hazards model (Cox) study. With the use of Gene Expression Omnibus, this study carried out gene set enrichment analysis (GSEA). In the meantime, the common miRNA database was compared to predict potential target genes; as revealed by co-expression analysis, a regulatory network probably existed, containing hsa-mir-3923. For the analysis of the most tightly associated cytological behavior and pathway in GC, this study adopted the databases for Annotation, Visualization and Integrated Discovery (David) and KO-Based Annotation System (KOBAS). Cytoscape, R and STRING were employed for mapping probable regulatory networks displaying relations to hsa-mir-3923. Lastly, we obtained 69 genes most tightly associated with hsa-mir-3923 and described their relationship with Circos plot. As revealed from the results, hsa-mir-3923 displayed up-regulation in gastric carcinoma, and it displayed associations with vital status, N stage and histologic grade when being expressed. The predicted results of miRNA target genes suggested that there may be a close relationship between 66 genes and hsa-mir-3923 in gastric cancer. As indicated from co-expression data, a small regulating network of 4 genes probably existed. Our results elucidated that hsa-mir-3923 high-expression reveals poor prognosis of GC patients.

Dataset Information

Aspartate β-Hydroxylase Serves as a Prognostic Biomarker for Neoadjuvant Chemotherapy in Gastric Cancer.

Publications

Aspartate β-Hydroxylase Serves as a Prognostic Biomarker for Neoadjuvant Chemotherapy in Gastric Cancer.

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