MicroRNA-27a-3p targets FoxO signalling to induce tumour-like phenotypes in bile duct cells
Year: 2022
Type: article
Abstract: BACKGROUND & AIMS: Cholangiocarcinoma (CCA) is a heterogeneous and lethal malignancy, the molecular origins of which remain poorly understood. MicroRNAs (miRs) target diverse signalling pathways, functioning as potent epigenetic regulators of transcriptional output. We aimed to characterise miRNome dysregulation in CCA, including its impact on transcriptome homeostasis and cell behaviour. METHODS: Small RNA sequencing was performed on 119 resected CCAs, 63 surrounding liver tissues, and 22 normal livers. High-throughput miR mimic screens were performed in three primary human cholangiocyte cultures. Integration of patient transcriptomes and miRseq together with miR screening data identified an oncogenic miR for characterization. MiR-mRNA interactions were investigated by a luciferase assay. MiR-CRISPR knockout cells were generated and phenotypically characterized in vitro (proliferation, migration, colony, mitochondrial function, glycolysis) and in vivo using subcutaneous xenografts. RESULTS: In total, 13% (140/1,049) of detected miRs were differentially expressed between CCA and surrounding liver tissues, including 135 that were upregulated in tumours. CCA tissues were characterised by higher miRNome heterogeneity and miR biogenesis pathway expression. Unsupervised hierarchical clustering of tumour miRNomes identified three subgroups, including distal CCA-enriched and IDH1 mutant-enriched subgroups. High-throughput screening of miR mimics uncovered 71 miRs that consistently increased proliferation of three primary cholangiocyte models and were upregulated in CCA tissues regardless of anatomical location, among which only miR-27a-3p had consistently increased expression and activity in several cohorts. FoxO signalling was predominantly downregulated by miR-27a-3p in CCA, partially through targeting of FOXO1. MiR-27a knockout increased FOXO1 levels in vitro and in vivo, impeding tumour behaviour and growth. CONCLUSIONS: The miRNomes of CCA tissues are highly remodelled, impacting transcriptome homeostasis in part through regulation of transcription factors like FOXO1. MiR-27a-3p arises as an oncogenic vulnerability in CCA. IMPACT AND IMPLICATIONS: Cholangiocarcinogenesis entails extensive cellular reprogramming driven by genetic and non-genetic alterations, but the functional roles of these non-genetic events remain poorly understood. By unveiling global miRNA upregulation in patient tumours and their functional ability to increase proliferation of cholangiocytes, these small non-coding RNAs are implicated as critical non-genetic alterations promoting biliary tumour initiation. These findings identify possible mechanisms for transcriptome rewiring during transformation, with potential implications for patient stratification.
Source: Journal of Hepatology
Authors: Lea Duwe, Patricia Munoz-Garrido, Monika Lewinska, Juan Lafuente-Barquero, Letizia Satriano, Dan Høgdall, Andrzej Taranta, Boye S. Nielsen, Awaisa Ghazal, Matthias S. Matter, Jesus M. Banales, Blanca I. Aldana, Yu-Tang Gao, Jens U. Marquardt, Lewis R. Roberts, Rui C. Oliveira, Jill Koshiol, Colm J. O'Rourke, Jesper B. Andersen
Institutions: University of Copenhagen, Herlev Hospital, Copenhagen University Hospital, Gentofte Hospital, Bioneer (Denmark), University Hospital of Basel, Ikerbasque, University of the Basque Country, Instituto de Salud Carlos III, Biogipuzkoa Health Research Institute, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas, Donostiako Unibertsitate Ospitalea, Universidad de Navarra, Shanghai Cancer Institute, University of Lübeck, Mayo Clinic, Unidade Local de Saúde de Coimbra, Centro de Investigação em Meio Ambiente Genética e Oncobiologia, University of Coimbra, Division of Cancer Epidemiology and Genetics
Language: English
Subfield: Surgery
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,500
Funders: National Science Foundation, PSC Partners Seeking a Cure, European Commission, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, Lundbeckfonden, Novo Nordisk, Dansk Kræftforsknings Fond, European Association for the Study of the Liver, Novo Nordisk Fonden, H. Lundbeck A/S, National Institutes of Health, Instituto de Salud Carlos III, European Regional Development Fund, National Cancer Institute
Awards: The role of the inflammatory microenvironment in liver cancer development, G2328893653, G2920270920, Papel del factor de transcripción KLF5 en la etiopatogenia del cáncer biliar: nueva estrategia diagnóstica, pronóstica y terapéutica, G434337789, G4369663061, Papel del factor de transcripción KLF15 en la etiopatogenia del cáncer biliar: nueva estrategia diagnóstica, pronóstica y terapéutica, European-Latin American network for the assessment of biomarkers to predict and diagnose hepatobiliary malignancies and characterization of risk factors for cancer development, G5934299761, G6374948078, G8508242418, G880118091, Mayo Clinic Hepatobiliary SPORE, Etiology of Biliary Tract Cancer, International Doctoral Programme in Molecular Mechanisms of Disease
OpenAlex ID: W4307723106