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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\u2010regulated genes in cholangiocarcinogenesis via BilIN. We used a clinicopathologically well\u2010characterised cohort of 12 dCCA patients. Matched samples of non\u2010neoplastic biliary epithelia, BilIN and invasive tumour epithelia of each patient were isolated from formalin\u2010fixed paraffin\u2010embedded 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\u00ae technology. Candidate miRNAs were validated by RT\u2010qPCR and functionally investigated following lentiviral overexpression in dCCA\u2010derived 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\u2010neoplastic 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\u2010451a (\u221210.9\u2010fold down) and miR\u2010144\u20103p (\u22126.3\u2010fold 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\u2010containing protein 10 (ADAM10) were identified as direct miR\u2010451a target genes. Specific ATF2 inhibition by pooled siRNAs reproduced the inhibitory impact of miR\u2010451a 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\u2010451a and miR\u2010144\u20103p as putative tumour suppressors attenuating cell migration by inhibiting <jats:italic>ATF2<\/jats:italic> in the process of dCCA tumorigenesis. \u00a9 The Authors. <jats:italic>The Journal of Pathology<\/jats:italic> published by John Wiley &amp; Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.<\/jats:p>","DOI":"10.1002\/path.5514","type":"journal-article","created":{"date-parts":[[2020,7,25]],"date-time":"2020-07-25T06:20:42Z","timestamp":1595658042000},"page":"239-251","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["<scp>miRNA<\/scp> profiling of biliary intraepithelial neoplasia reveals stepwise tumorigenesis in distal cholangiocarcinoma via the <scp>miR<\/scp>\u2010451a\/<scp>ATF2<\/scp> axis"],"prefix":"10.1002","volume":"252","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0267-2762","authenticated-orcid":false,"given":"Moritz A","family":"Loeffler","sequence":"first","affiliation":[{"name":"Institute of Pathology University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Hu","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martina","family":"Kirchner","sequence":"additional","affiliation":[{"name":"Institute of Pathology University Hospital Heidelberg  Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiyang","family":"Wei","sequence":"additional","affiliation":[{"name":"Life Sciences Institute Zhejiang University  Hangzhou PR 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