PS-132 Characterization of miR deregulation in cholangiocarcinoma (CCA): Consequences in tumor heterogeneity and drug resistance P. Munoz-Garrido 1,2 , L. Satriano 1 , D. Høgdall 1,3 , J. Banales 4 , A. Ghazal 1 , C.O. Rourke 4 , J. Andersen 1 , J. Marquardt 5 . 1 Biotech Research & Innovation Center (BRIC), Health Science Faculty, University of Copenhagen, Copenhagen N, Denmark; 2 * Sheilla Sherlock Fellow; 3 Herlev and Gentofte Hospital, Copenhagen University Hospital, Department of Oncology, Herlev, Denmark; 4 Biodonostia Research Institute, Department of Liver Diseases, San Sebastian, Spain, 5 Biotech Research & Innovation Center (BRIC), Health Science Faculty, University of Copenhagen, Copenhagen, Denmark; 6 Johannes Gutenberg University, Department of Medicine I, Lichtenberg Research Group, Mainz, Germany Email: jesper.andersen@bric.ku.dk Background and Aims: A characteristic hallmark of cholangiocarci- noma (CCA) is its genomic heterogeneity, which inevitably manifests in therapeutic resistance. The molecular mechanisms driving tumorigenesis, and the basis for why CCA malignancies demonstrate resistance remains unclear. We elucidate the deregulated miR landscape in a CCA patient cohort characterizing the miR involve- ment in disease onset and role in eliciting drug resistance. Method: Illumina small RNAseq (miRseq) was performed at high coverage (avg. 30M reads) in 212 fresh frozen samples. Also, for in vitro modeling,18 CCA and normal cell lines were analyzed. Patient- matched gene expression and mutational profiles of all CCA samples were generated. Integration of deregulated miR and aberrant gene expression was performed. High throughput screening (HTS) of >2,700 miR mimics was analyzed in primary normal human cholangiocyte (NHC) and patient-derived CCA cells evaluating their role in regulating proliferation and morphology. Gemcitabine resistant CCA cell lines were established to elucidate the role of miRs in drug refractory disease. Results: To distinguish deregulated miR expression in CCA, samples were divided into intrahepatic (iCCA, n = 99), perihilar (pCCA, n = 10) and distal disease (dCCA, n = 18), including matched adjacent tissues (n = 63) and normal controls (n = 23). Determination of deregulated miRs was performed bya well-established miR workflow (miRDeep2/ DEseq2). Data was processed with cutoffs of Padj.< 0.01 and IFC > 2. We have defined a total of 29 significant miRs (19 up and 10 down) in tumor samples compared to matched adjacent tissues (AUC = 0.99). Correlation of aberrantly expressed miRs and best fit model system was evaluated to manipulate select miRs and by HTS. Gene expression and mutational profiles of CCAs and adjacent normal tissue were analyzed and integrated with miRs. In the miR mimics library screen siAKT (decreased proliferation) and taurocholic acid (increased proliferation) were used as controls. Morphological changes were analyzed by fluorescent phalloidin membrane staining. Screening of NHC cells revealed 50 miRs that significantly increased the normal proliferation rate, of which mir-26b is a positive control known to be elevated in CCA. Additionally, 35 miRs significantly inhibited cellular proliferation and will be evaluated further as putative targets in CCA. Conclusion: The results obtained in this study provide new biological and molecular knowledge on CCA heterogeneity and lead to improve the current understanding of the pathobiology of miR-driven chemoresistance. Further analyses focused on identifying novel drug targets will bring miR biology forward as a therapeutic aim in CCA. PS-133 Novel role of amphiregulin in bile acids metabolism and protection from cholestatic liver injury E. Santamaria 1 , C. Rodriguez-Ortigosa 1 , I. Uriarte 1 , M.U. Latasa 1 , R. Urtasun 1 , B. Sangro 2 , P. Milkiewicz 3,4 , M. Milkiewicz 5 , M. Monte 6 , J. Marin 6 , M.G. Fernandez-Barrena 7 , Matías Avila 1 , C. Berasain 7 . 1 CIMA-University of Navarra. CIBERehd, IdiSNA, Hepatology, Pamplona, Spain; 2 Clinica Universidad de Navarra and CIBERehd, Liver Unit, Pamplona, Spain; 3 Medical University of Warsaw, Liver and Internal Medicine Unit, Warsaw, Poland; 4 Pomeranian Medical University, Translational Medicine Group, Szczecin, Poland; 5 Pomeranian Medical University, Department of Medical Biology, Szczecin, Poland; 6 University of Salamanca, IBSAL, CIBERehd, Dept. Physiology and Pharmacology, Salamanca, Spain; 7 CIMA-University of Navarra. CIBERehd, IdiSNA., Hepatology Email: maavila@unav.es Background and Aims: Many acute and chronic liver diseases are accompanied by cholestasis. Intrahepatic accumulation of bile acids (BAs) may cause hepatocytes and cholangiocytes death. Upon liver injury, a potent protective and regenerative response is mounted to restore the architecture and function of the organ. However, when this reparative reaction chronifies liver fibrosis and tumorigenesis may ensue. A better understanding of this reaction is required to devise hepatoprotective strategies, as well as antifibrogenic and antineoplastic therapies. The epidermal growth factor receptor (EGFR) signaling system is essential for regeneration after most types of experimental liver injury, including cholestatic injury. EGFR can be activated by a wide family of growth factors, among which amphiregulin (AR) was identified as a key mediator of liver regeneration. Here we have studied the role of AR during cholestatic liver injury and the mutual regulation of AR expression and BA synthesis. Method: We used two models of cholestatic liver injury: bile duct ligation (BDL) and oral alpha-naphtyl-isothiocyanate (ANIT) admin- istration in wild type (AR-WT) and AR knockout (AR-KO) mice. AR expression was examined in: (i) livers from patients with primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC); (ii) mice and cultured liver cells treated with BAs; and (iii) farnesoid X receptor knockout mice (FXR-KO) after BDL. The cytoprotective capacity of AR was evaluated in vitro and in vivo. Results: AR mRNA and protein were up-regulated in the liver of PBC and PSC patients (hepatocytes and cholangiocytes). Oral BA admin- istration to mice induces ileal and hepatic AR expression, and cholestyramine feeding reduces postprandial ileal and liver AR upregulation. AR-KO mice display higher Cyp7a1 expression and intrahepatic BA concentrations than AR-WT mice. Liver AR expression was markedly enhanced in BDL and ANIT groups of AR-WT mice. Liver damage was markedly exacerbated in AR-KOs. BAs induced AR expression in cultured liver cells partially through FXR. Consistently, after BDL FXR-KO mice show reduced liver ARexpression than FXR- WT. AR treatment protected from BDL-induced liver injury and from BAs toxicity in cultured liver cells. Conclusion: AR participates in BA homeostasis under physiological conditions. Liver AR expression is activated during cholestasis partially through FXR. AR plays an important role in protecting the liver from BA induced toxicity. PS-134 International experience of vedolizumab in primary sclerosis cholangitis and inflammatory bowel disease K. Williamson 1 , E. Lytvyak 2 , A.E. Kremer 3 , M. de Krijger 4 , P. Trivedi 5 , D. Estes 6 , L. Yu 7 , D. Pratt 8 , A. de Vries 9 , K.K. Yimam 10 , L. Daretti 11 , C.H. Liu 12 , C. Bowlus 12 , M. Vetter 3 , H.-U. Marschall 13 , A. Montano-Loza 14 , R.W.G. Chapman 15 , M. Marzioni 11 , S. Keshav 15 , C. Ponsioen 16 , G. Hirschfield 5 , C. Levy 17 and on belalf of PSC Study Group. 1 University of Oxford, Translational Gastroenterology Unit, Oxford, United Kingdom; 2 University of Alberta, Division of Gastroenterology, Edmonton, Canada; 3 Friedrich-Alexander-University, Department of Medicine, Erlangen, Germany; 4 Academic Medical Center, Department of Gastroenterology and Hepatology, Amsterdam, Netherlands; 5 University of Birmingham, Centre for Liver Research and NIHR Biomedical Research Centre, Birmingham, United Kingdom; 6 University of Miami, Division of Hepatology, Miami, United States; 7 University of Washington Medical Center, Liver Care & Transplantation Services, Seattle, United States; 8 Massachusetts General Hospital, ORAL PRESENTATIONS S74 Journal of Hepatology 2018 vol. 68 | S65–S104