Scheiter, A.A.ScheiterEvert, K.K.EvertReibenspies, L.L.ReibenspiesCigliano, A.A.CiglianoAnnweiler, K.K.AnnweilerMüller, K.K.MüllerPöhmerer, L.-M.-G.L.-M.-G.PöhmererXu, H.H.XuCui, G.G.CuiItzel, T.T.ItzelMaterna-Reichelt, S.S.Materna-ReicheltColuccio, A.A.ColuccioHonarnejad, K.K.HonarnejadTeufel, A.A.TeufelBrochhausen, C.C.BrochhausenDombrowski, F.F.DombrowskiChen, X.X.ChenEvert, M.M.EvertCalvisi, D.F.D.F.CalvisiUtpatel, K.K.Utpatel2022-05-062022-05-062022https://publica.fraunhofer.de/handle/publica/41569710.1002/1878-0261.131352-s2.0-85120541851Aberrant activation of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR and Ras/mitogen-activated protein kinase (MAPK) pathways is a hallmark of hepatocarcinogenesis. In a subset of hepatocellular carcinomas (HCCs), PI3K/AKT/mTOR signaling dysregulation depends on phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutations, while RAS/MAPK activation is partly attributed to promoter methylation of the tumor suppressor Ras association domain-containing protein 1 (RASSF1A). To evaluate a possible cocarcinogenic effect of PIK3CA activation and RASSF1A knockout, plasmids expressing oncogenic forms of PIK3CA (E545K or H1047R mutants) were delivered to the liver of RASSF1A knockout and wild-type mice by hydrodynamic tail vein injection combined with sleeping beauty-mediated somatic integration. Transfection of either PIK3CA E545K or H1047R mutants sufficed to induce HCCs in mice irrespective of RASSF1A mutational background. The related tumors displayed a lipogenic phenotype with upregulation of fatty acid synthase and stearoyl-CoA desaturase-1 (SCD1). Galectin-1, which was commonly upregulated in preneoplastic lesions and tumors, emerged as a regulator of SCD1. Co-inhibitory treatment with PIK3CA inhibitors and the galectin-1 inhibitor OTX008 resulted in synergistic cytotoxicity in human HCC cell lines, suggesting novel therapeutic venues.en610620journal article