Project description:Genome-wide expression analysis of 182 extrahepatic cholangiocarcinoma and 38 non-tumoral bile duct samples as part of a integrated study of gene expression and targeted DNA-sequencing in patients with extrahepatic cholangiocarcinoma We used whole-genome transcriptome to conduct an unsupervised molecular classification of extrahepatic cholangiocarcinoma
Project description:Biliary tract cancer (BTC) ranks among the most lethal human malignancies, thereby representing an unmet clinical need. In this study, we find that the Pdx1-positive extrahepatic biliary epithelium is highly susceptible towards transformation by activated Pik3caH1047R, but completely refractory to oncogenic KrasG12D. Using genome-wide in vivo piggyBac transposon-based forward genetic screening and genetic loss-of-function experiments, we discover important extrahepatic cholangiocarcinoma (ECC) cancer genes and find that PI3K-signaling output strength and repression of the tumor suppressor p27Kip1 are critical context-specific determinants of tumor formation. This contrasts the pancreas, where oncogenic Kras in concert with Trp53 loss of function are key cancer drivers. Notably, inactivation of p27Kip1 permits KrasG12D-driven ECC development, and bypasses oncogene-induced senescence without triggering the Trp53 pathway. These studies provide a mechanistic link between PI3K-signaling, tissue-specific tumor suppressor barriers, and ECC pathogenesis, and present a novel genetic model of autochthonous ECC and genes driving this highly lethal tumor-subtype.
Project description:To identify miRNAs differentially expressed in cholangiocarcinoma,3 human cholangiocarcinoma and their corresponding normal bile duct tissues were obtained from 3 patients after operation with postoperative pathological diagnosed perihilar or distal biliary cholangiocarcinoma
Project description:Cholangiocarcinoma (CCA) and pancreatic adenocarcinoma (PDAC) may lead to the development of extrahepatic obstructive cholestasis. However, biliary stenoses can also be caused by benign conditions, and the identification of their etiology still remains a clinical challenge. We performed metabolomic and proteomic analyses of bile from patients with benign (n=36) and malignant conditions, CCA (n=36) or PDAC (n=57), undergoing endoscopic retrograde cholangiopancreatography with the aim of characterizing bile composition in biliopancreatic disease and identifying biomarkers for the differential diagnosis of biliary strictures. Comprehensive analyses of lipids, bile acids and small molecules were carried out using mass spectrometry (MS) and nuclear magnetic resonance spectroscopy (1H-NMR) in all patients. MS analysis of bile proteome was performed in five patients per group. We implemented artificial intelligence tools for the selection of biomarkers and algorithms with predictive capacity. Our machine-learning pipeline included the generation of synthetic data with properties of real data, the selection of potential biomarkers (metabolites or proteins) and their analysis with neural networks (NN). Selected biomarkers were then validated with real data. We identified panels of lipids (n=10) and proteins (n=5) that when analyzed with NN algorithms discriminated between patients with and without cancer with an unprecedented accuracy.
Project description:To identify miRNAs differentially expressed in cholangiocarcinoma,3 human cholangiocarcinoma and their corresponding normal bile duct tissues were obtained from 3 patients after operation with postoperative pathological diagnosed perihilar or distal biliary cholangiocarcinoma miRNAs expression in human cholangiocarcinoma/normal bile duct samples was measured after operation.Three independent experiments were performed using different patients for each experiment.
Project description:The overall objective of this study was to explore aberrantly expressed microRNAs (miRNAs) and investigate their clinical significances in patients with extrahepatic cholangiocarcinoma (ECCA).
Project description:Biliary tract cancer (BTC) has poor prognosis. The Notch receptor is aberrantly expressed in extrahepatic cholangiocarcinoma (eCCA). However, the role of Notch signaling in the initiation and progression of eCCA and gallbladder (GB) cancer remains unknown. We investigated the functional role of Notch signaling during tumorigenesis of the extrahepatic bile duct and GB. We demonstrated that simultaneous activation of the Kras–Akt and Notch pathways in EHBD and GB resulted in the formation of BilINs and biliary cancer in a mouse model. Mechanistically, the Kras/Notch–Myc axis activates mTORC1 through phosphorylation of TSC2 in biliary tumorigenesis.
Project description:Cholangiocarcinoma (CCA) is a type of highly aggressive cancer arising from the biliary system. Through serum exosome miRNA sequencing, we screened out the differentially expressed miRNA in patients with cholangiocarcinoma(CCA) and common bile duct stones(CBDS).
Project description:Homeobox A5 (HOXA5) is a transcription factor in mammalian and can regulate cell differentiation, proliferation and apoptosis as well as tumorigenesis. However, little is known on whether and how HOXA5 can regulate the malignant behaviors of cholangiocarcinoma. The methylation levels of HOXA5 were evaluated by methylation microarray and bisulfite sequencing PCR. We found that hypermethylation in the HOXA5 promoter down-regulated HOXA5 expression in extrahepatic cholangiocarcinoma (ECCA) tissues, which was correlated with worse overall survival. HOXA5 over-expression significantly inhibited the proliferation and tumor growth.
Project description:Gut dysbiosis is closely involved in the pathogenesis of inflammatory bowel disease (IBD). However, it remains unclear whether IBD-associated gut dysbiosis plays a primary role in disease manifestation or is merely secondary to intestinal inflammation. Here, we established a humanized gnotobiotic (hGB) mouse system to assess the functional role of gut dysbiosis associated with two types of IBD - Crohn's disease (CD) and ulcerative colitis (UC). In order to explore the functional impact of dysbiotic microbiota in IBD patients on host immune responses, we analyzed gene expression profiles in colonic mucosa of hGB mice colonized with healty (HC), CD, and UC microbiota.