Molecular profiling reveals potential targets in cholangiocarcinoma

作     者：Dan Liu Yang Shi Hongze Chen Muhammad Azhar Nisar Nicholas Jabara Noah Langwinski Sophia Mattson Katsuya Nagaoka Xuewei Bai Shaolei Lu Chiung-Kuei Huang 

作者机构：Department of GastroenterologyThe First Affiliated Hospital of Zhengzhou UniversityZhengzhou 450052Henan ProvinceChina Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLA 70112United States Department of MedicineRhode Island Hospital and the Alpert Medical School of Brown UniversityProvidenceRI 02903United States Department of PathologyAlpert Medical School of Brown UniversityProvidenceRI 02903United States 

出 版 物：《World Journal of Gastroenterology》 (世界胃肠病学杂志（英文版）)

年 卷 期：2023年第29卷第25期

页      面：4053-4071页

核心收录：

学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学] 

基　　金：Supported by 2017 AASLD Pinnacle Research Career Development Award 

主　　题：Bile duct cancer Notch Cell cycle Liver cancer Therapeutic target 

摘      要：BACKGROUND Cholangiocarcinoma(CCA)is a devastating malignancy and has a very poor prognosis if tumors spread outside the *** the molecular mechanisms underlying the CCA progression will likely yield therapeutic approaches toward treating this deadly *** To determine the molecular pathogenesis in CCA *** In silico analysis,in vitro cell culture,CCA transgenic animals,histological,and molecular assays were adopted to determine the molecular *** The transcriptomic data of human CCA samples were retrieved from The Cancer Genome Atlas(TGCA,CHOL),European Bioinformatics Institute(EBI,GAD-00001001076),and Gene Expression Omnibus(GEO,GSE107943)*** Gene set enrichment analysis,the cell cycle and Notch related pathways were demonstrated to be significantly activated in CCA in TCGA and GEO ***,through differentially expressed genes,found several cell cycle and notch associated genes were significantly up-regulated in cancer tissues when compared with the non-cancerous control *** associated genes,via quantitative real-time PCR and western blotting assays,were further examined in normal human cholangiocytes,CCA cell lines,mouse normal bile ducts,and mouse CCA tumors established by specifically depleting P53 and expressing KrasG12D mutation in the ***,we validated that the cell cycle and Notch pathways are up-regulated in CCA cell lines and mouse CCA ***,targeting cell cycle and notch pathways using small molecules also exhibited significant beneficial effects in controlling tumor *** importantly,we demonstrated that several cell cycle and Notch associated genes are significantly associated with poor overall survival and disease-free survival using the Log-Rank *** In summary,our study comprehensively analyzed the gene expression pattern of CCA samples using publicly available datasets and identified the cell cycle and Notch pathways are po