<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "The role of tumor suppressor genes PBRM1 and RPS6KA3 in primary liver cancer"^^ . "Primary liver cancer (PLC) is a major health concern, being the fifth most occurring \r\ncancer and the second most lethal worldwide. However, due to the lack of targetable \r\nmutations in patient tumors, treatment options are still limited. Therefore, identifying and \r\ncharacterizing new targetable mutations in PLC is of the utmost importance. In the present \r\nstudy, I interrogated publicly available human PLC sequencing data to detect and functionally \r\ncharacterize recurring genetic alterations, with the overall aim of identifying potential \r\nbiomarkers exploitable by precision medicine.\r\nPBRM1 is a component of the SWI/SNF epigenetic remodeling complexes and was \r\nfound to be preferentially mutated in intrahepatic cholangiocarcinoma (iCCA) rather than \r\nhepatocellular carcinoma (HCC), thus suggesting a role as tumor initiator and/or cancer \r\nidentity determinator. To gain further insight, I employed mouse models with liver-specific \r\ndeletion or reversible downregulation of PBRM1 by CRISPR/Cas9 or RNA interference, \r\nrespectively. In parallel, loss of PBRM1 was further investigated in these mouse models with \r\nNASH-inducing dietary models of HCC. Disrupting PBRM1 expression in vivo and in vitro\r\nshowed no connection between PBRM1 expression status and its involvement in liver cancer \r\ninitiation or liver cancer plasticity. \r\nRPS6KA3 is a kinase protein that acts as an effector and negative feedback regulator of \r\nRAS/MAPK pathway. The results from this dissertation demonstrated that RPS6KA3 loss \r\ncontributes to tumorigenicity in vivo and that the loss of RPS6KA3 leads to an upregulation of \r\nthe MAPK pathway both in vivo and in vitro with murine and human HCC cell lines. Moreover, \r\nRPS6KA3-depleted murine xenograft tumors and orthotopically transplanted human HCC cells \r\nlines with low RPS6KA3 levels responded remarkably to trametinib, a FDA-approved MEK \r\ninhibitor. Thus, the results not only reveal RPS6KA3 as an important tumor suppressor in HCC \r\nbut also implicate RPS6KA3 as a novel biomarker for MAPK pathway inhibitors in HCC patients."^^ . "2022" . . . . . . . "Leonardo"^^ . "Traini"^^ . "Leonardo Traini"^^ . . . . . . "The role of tumor suppressor genes PBRM1 and RPS6KA3 in primary liver cancer (PDF)"^^ . . . "Traini_PhD_Thesis_Final.pdf"^^ . . . "The role of tumor suppressor genes PBRM1 and RPS6KA3 in primary liver cancer (Other)"^^ . . . . . . "indexcodes.txt"^^ . . . "The role of tumor suppressor genes PBRM1 and RPS6KA3 in primary liver cancer (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "The role of tumor suppressor genes PBRM1 and RPS6KA3 in primary liver cancer (Other)"^^ . . . . . . "preview.jpg"^^ . . . "The role of tumor suppressor genes PBRM1 and RPS6KA3 in primary liver cancer (Other)"^^ . . . . . . "medium.jpg"^^ . . . "The role of tumor suppressor genes PBRM1 and RPS6KA3 in primary liver cancer (Other)"^^ . . . . . . "small.jpg"^^ . . "HTML Summary of #31195 \n\nThe role of tumor suppressor genes PBRM1 and RPS6KA3 in primary liver cancer\n\n" . "text/html" . .