miRNA profiling of biliary intraepithelial neoplasia reveals stepwise tumorigenesis in distal cholangiocarcinoma via the miR-451a/ATF2 axis.

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Abstrakt

Tytuł:: miRNA profiling of biliary intraepithelial neoplasia reveals stepwise tumorigenesis in distal cholangiocarcinoma via the miR-451a/ATF2 axis.
Autorzy:: Loeffler MA; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Hu J; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Kirchner M; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
Wei X; Life Sciences Institute, Zhejiang University, Hangzhou, PR China.
Xiao Y; Life Sciences Institute, Zhejiang University, Hangzhou, PR China.
Albrecht T; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
De La Torre C; Medical Research Centre, University of Heidelberg, Mannheim, Germany.
Sticht C; Medical Research Centre, University of Heidelberg, Mannheim, Germany.
Banales JM; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, San Sebastian, Spain.
Vogel MN; Diagnostic and Interventional Radiology, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
Pathil-Warth A; Department of Internal Medicine IV, Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany.
Mehrabi A; Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.; Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.
Hoffmann K; Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.; Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.
Rupp C; Department of Internal Medicine IV, Gastroenterology and Hepatology, University Hospital Heidelberg, Heidelberg, Germany.; Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.
Köhler B; Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.; Department of Medical Oncology, University Hospital Heidelberg, National Center for Tumor Diseases, Heidelberg, Germany.
Springfeld C; Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.; Department of Medical Oncology, University Hospital Heidelberg, National Center for Tumor Diseases, Heidelberg, Germany.
Schirmacher P; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.; Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.
Ji J; Life Sciences Institute, Zhejiang University, Hangzhou, PR China.
Roessler S; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.; Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.
Goeppert B; Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.; Liver Cancer Center Heidelberg (LCCH), Heidelberg, Germany.
Źródło:: The Journal of pathology [J Pathol] 2020 Nov; Vol. 252 (3), pp. 239-251. Date of Electronic Publication: 2020 Sep 15.
Typ publikacji:: Journal Article; Research Support, Non-U.S. Gov't
Język:: English
Imprint Name(s):: Publication: Chichester : John Wiley And Sons
Original Publication: London, Oliver & Boyd.
MeSH Terms:: Gene Expression Regulation, Neoplastic*
Activating Transcription Factor 2/*metabolism
Bile Duct Neoplasms/*genetics
Biomarkers, Tumor/*genetics
Carcinoma in Situ/*genetics
Cholangiocarcinoma/*genetics
MicroRNAs/*metabolism
ADAM10 Protein/metabolism ; Amyloid Precursor Protein Secretases/metabolism ; Bile Duct Neoplasms/metabolism ; Bile Duct Neoplasms/pathology ; Bile Ducts, Extrahepatic/metabolism ; Bile Ducts, Extrahepatic/pathology ; Biomarkers, Tumor/metabolism ; Carcinogenesis/genetics ; Carcinoma in Situ/metabolism ; Carcinoma in Situ/pathology ; Case-Control Studies ; Cell Movement/genetics ; Cholangiocarcinoma/metabolism ; Cholangiocarcinoma/pathology ; Down-Regulation ; Female ; Gene Expression Profiling ; Humans ; Male ; Membrane Proteins/metabolism
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Contributed Indexing:: Keywords: ATF2; biliary intraepithelial neoplasia; cell invasion; cell migration; cholangiocarcinogenesis; cholangiocarcinoma; miR-144-3p; miR-451a; miRNA; precursor lesion
Substance Nomenclature:: 0 (ATF2 protein, human)
0 (Activating Transcription Factor 2)
0 (Biomarkers, Tumor)
0 (MIRN144 microRNA, human)
0 (MIRN451 microRNA, human)
0 (Membrane Proteins)
0 (MicroRNAs)
EC 3.4.- (Amyloid Precursor Protein Secretases)
EC 3.4.24.81 (ADAM10 Protein)
EC 3.4.24.81 (ADAM10 protein, human)
Entry Date(s):: Date Created: 20200726 Date Completed: 20201217 Latest Revision: 20201217
Update Code:: 20240104
DOI:: 10.1002/path.5514
PMID:: 32710569
: Czasopismo naukowe

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Distal cholangiocarcinoma (dCCA) is a biliary tract cancer with a dismal prognosis and is often preceded by biliary intraepithelial neoplasia (BilIN), representing the most common biliary non-invasive precursor lesion. BilIN are histologically well defined but have not so far been characterised systematically at the molecular level. The aim of this study was to determine miRNA-regulated genes in cholangiocarcinogenesis via BilIN. We used a clinicopathologically well-characterised cohort of 12 dCCA patients. Matched samples of non-neoplastic biliary epithelia, BilIN and invasive tumour epithelia of each patient were isolated from formalin-fixed paraffin-embedded tissue sections by laser microdissection. The resulting 36 samples were subjected to total RNA extraction and the expression of 798 miRNAs was assessed using the Nanostring® technology. Candidate miRNAs were validated by RT-qPCR and functionally investigated following lentiviral overexpression in dCCA-derived cell lines. Potential direct miRNA target genes were identified by microarray and prediction algorithms and were confirmed by luciferase assay. We identified 49 deregulated miRNAs comparing non-neoplastic and tumour tissue. Clustering of these miRNAs corresponded to the three stages of cholangiocarcinogenesis, supporting the concept of BilIN as a tumour precursor. Two downregulated miRNAs, i.e. miR-451a (-10.9-fold down) and miR-144-3p (-6.3-fold down), stood out by relative decrease. Functional analyses of these candidates revealed a migration inhibitory effect in dCCA cell lines. Activating transcription factor 2 (ATF2) and A disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) were identified as direct miR-451a target genes. Specific ATF2 inhibition by pooled siRNAs reproduced the inhibitory impact of miR-451a on cancer cell migration. Thus, our data support the concept of BilIN as a direct precursor of invasive dCCA at the molecular level. In addition, we identified miR-451a and miR-144-3p as putative tumour suppressors attenuating cell migration by inhibiting ATF2 in the process of dCCA tumorigenesis. © The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
(© The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.)

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