miRNA profiling of biliary intraepithelial neoplasia reveals stepwise tumorigenesis in distal cholangiocarcinoma via the miR-451a/ATF2 axis.
ADAM10 Protein
/ metabolism
Activating Transcription Factor 2
/ metabolism
Amyloid Precursor Protein Secretases
/ metabolism
Bile Duct Neoplasms
/ genetics
Bile Ducts, Extrahepatic
/ metabolism
Biomarkers, Tumor
/ genetics
Carcinogenesis
/ genetics
Carcinoma in Situ
/ genetics
Case-Control Studies
Cell Movement
/ genetics
Cholangiocarcinoma
/ genetics
Down-Regulation
Female
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Male
Membrane Proteins
/ metabolism
MicroRNAs
/ metabolism
ATF2
biliary intraepithelial neoplasia
cell invasion
cell migration
cholangiocarcinogenesis
cholangiocarcinoma
miR-144-3p
miR-451a
miRNA
precursor lesion
Journal
The Journal of pathology
ISSN: 1096-9896
Titre abrégé: J Pathol
Pays: England
ID NLM: 0204634
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
19
12
2019
revised:
30
05
2020
accepted:
17
07
2020
pubmed:
28
7
2020
medline:
18
12
2020
entrez:
26
7
2020
Statut:
ppublish
Résumé
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.
Substances chimiques
ATF2 protein, human
0
Activating Transcription Factor 2
0
Biomarkers, Tumor
0
MIRN144 microRNA, human
0
MIRN451 microRNA, human
0
Membrane Proteins
0
MicroRNAs
0
Amyloid Precursor Protein Secretases
EC 3.4.-
ADAM10 Protein
EC 3.4.24.81
ADAM10 protein, human
EC 3.4.24.81
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
239-251Informations de copyright
© 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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