{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T23:05:57Z","timestamp":1790809557787,"version":"4.1.0"},"reference-count":41,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2019,10,31]],"date-time":"2019-10-31T00:00:00Z","timestamp":1572480000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Liver International"],"published-print":{"date-parts":[[2020,1]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Therapeutic outcomes using the multikinase inhibitors, sorafenib and regorafenib, remain unsatisfactory for patients with advanced hepatocellular carcinoma (HCC). Thus, new drug modalities are needed. We recently reported the remarkable capacity of miR\u20104510 to impede the growth of HCC and hepatoblastoma through <jats:italic>Glypican\u20103<\/jats:italic> (GPC3) targeting and Wnt pathway inactivation.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>To identify new targets of miR\u20104510, we used a label\u2010free proteomic approach and reported down\u2010regulation of RAF proto\u2010oncogene serine\/threonine\u2010protein kinase (RAF1) by miR\u20104510. Because the tumourigenic role of RAF1 in HCC is controversial, we further studied <jats:italic>RAF1<\/jats:italic>:miR\u20104510 interactions using cellular, molecular as well as functional approaches and a chicken chorioallantoic membrane (CAM) xenograft model.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We found an increase in RAF1 protein in 59.3% of HCC patients and a specific up\u2010regulation of its transcript in proliferative tumours. We showed that miR\u20104510 inactivates the RAS\/RAF\/MEK\/ERK pathway and reduces the expression of downstream targets (ie c\u2010Fos proto\u2010oncogene [FOS]) through <jats:italic>RAF1<\/jats:italic> direct targeting. At a cellular level, miR\u20104510 inhibited HCC cell proliferation and migration and induced senescence in part by lowering RAF1 messenger RNA (mRNA) and protein expression. Finally, we confirmed the pro\u2010tumoural function of RAF1 protein in HCC cells and its ability to sustain HCC tumour progression in vitro and in vivo.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>In this work, we confirm that RAF1 acts as an oncogene in HCC and further demonstrate that miR\u20104510 acts as a strong tumour suppressor in the liver by targeting many proto\u2010oncogenes, including <jats:italic>GPC3<\/jats:italic> and <jats:italic>RAF1,<\/jats:italic> and subsequently controlling key biological and signalling pathways among which Wnt and RAS\/RAF\/MEK\/ERK signals.<\/jats:p><\/jats:sec>","DOI":"10.1111\/liv.14276","type":"journal-article","created":{"date-parts":[[2019,10,15]],"date-time":"2019-10-15T05:29:11Z","timestamp":1571117351000},"page":"240-251","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["miR\u20104510 blocks hepatocellular carcinoma development through <i>RAF1<\/i> targeting and RAS\/RAF\/MEK\/ERK signalling inactivation"],"prefix":"10.1111","volume":"40","author":[{"given":"Amani","family":"Ghousein","sequence":"first","affiliation":[{"name":"Inserm BMGIC U1035 Univ. Bordeaux Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Mosca","sequence":"additional","affiliation":[{"name":"Inserm BMGIC U1035 Univ. Bordeaux Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Flora","family":"Cartier","sequence":"additional","affiliation":[{"name":"Inserm BMGIC U1035 Univ. Bordeaux Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justine","family":"Charpentier","sequence":"additional","affiliation":[{"name":"Inserm BMGIC U1035 Univ. Bordeaux Bordeaux France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean\u2010William","family":"Dupuy","sequence":"additional","affiliation":[{"name":"Centre de G\u00e9nomique Fonctionnelle de Bordeaux Plateforme Proteome Univ. 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