Scheiter, Alexander and Evert, Katja and Reibenspies, Lucas and Cigliano, Antonio and Annweiler, Katharina and Mueller, Karolina and Poehmerer, Laura-Maria-Giovanna and Xu, Hongwei and Cui, Guofei and Itzel, Timo and Materna-Reichelt, Silvia and Coluccio, Andrea and Honarnejad, Kamran and Teufel, Andreas and Brochhausen, Christoph and Dombrowski, Frank and Chen, Xin and Evert, Matthias and Calvisi, Diego F. and Utpatel, Kirsten (2022) RASSF1A independence and early galectin-1 upregulation in PIK3CA-induced hepatocarcinogenesis: new therapeutic venues. MOLECULAR ONCOLOGY, 16 (5). pp. 1091-1118. ISSN 1574-7891, 1878-0261
Full text not available from this repository. (Request a copy)Abstract
Aberrant 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | TUMOR-SUPPRESSOR RASSF1A; HEPATOCELLULAR-CARCINOMA; MOUSE MODELS; PPAR-GAMMA; ACTIVATION; LIVER; RAS; PIK3CA; FAMILY; GROWTH; alpelisib; galectin-1; hepatocellular carcinoma; OTX008; SCD1; ZIP4 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie Medicine > Zentren des Universitätsklinikums Regensburg > Zentrum für Klinische Studien |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 06 Sep 2022 06:53 |
| Last Modified: | 06 Sep 2022 06:53 |
| URI: | https://pred.uni-regensburg.de/id/eprint/46650 |
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