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RASSF1A independence and early Galectin-1 upregulation in PIK3CA induced hepatocarcinogenesis: new therapeutic venues

By Alexander Scheiter, Katja Evert, Lucas Reibenspies, Antonio Cigliano, Katharina Annweiler, Karolina Mueller, Laura-Maria-Giovanna Poehmerer, Timo Itzel, Silvia Materna-Reichelt, Andrea Coluccio, Kamran Honarnejad, Andreas Teufel, Christoph Brochhausen, Frank Dombrowski, Xin Chen, Matthias Evert, Diego Calvisi, Kirsten Utpatel

Posted 15 Jun 2021
bioRxiv DOI: 10.1101/2021.06.15.448477

Aberrant activation of the PI3K/AKT/mTOR and Ras/Mitogen-Activated Protein Kinase pathways is a hepatocarcinogenesis hallmark. In a subset of hepatocellular carcinomas (HCC), PI3K/AKT/mTOR signaling dysregulation depends on PIK3CA mutations, while RAS/MAPK activation is partly attributed to promoter methylation of the tumor suppressor RASSF1A. To evaluate a possible co-carcinogenic 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 wildtype mice by hydrodynamic tail vein injection combined with Sleeping Beauty-mediated somatic integration. Transfection of either PIK3CA E545K or H1047R mutants sufficed to induce hepatocellular carcinomas 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 OTX-008 resulted in synergistic cytotoxicity in human HCC cell lines, suggesting novel therapeutic venues.

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