TY  - GEN
Y1  - 2022///
ID  - heidok31195
UR  - https://archiv.ub.uni-heidelberg.de/volltextserver/31195/
CY  - Heidelberg
A1  - Traini, Leonardo
N2  - Primary liver cancer (PLC) is a major health concern, being the fifth most occurring 
cancer and the second most lethal worldwide. However, due to the lack of targetable 
mutations in patient tumors, treatment options are still limited. Therefore, identifying and 
characterizing new targetable mutations in PLC is of the utmost importance. In the present 
study, I interrogated publicly available human PLC sequencing data to detect and functionally 
characterize recurring genetic alterations, with the overall aim of identifying potential 
biomarkers exploitable by precision medicine.
PBRM1 is a component of the SWI/SNF epigenetic remodeling complexes and was 
found to be preferentially mutated in intrahepatic cholangiocarcinoma (iCCA) rather than 
hepatocellular carcinoma (HCC), thus suggesting a role as tumor initiator and/or cancer 
identity determinator. To gain further insight, I employed mouse models with liver-specific 
deletion or reversible downregulation of PBRM1 by CRISPR/Cas9 or RNA interference, 
respectively. In parallel, loss of PBRM1 was further investigated in these mouse models with 
NASH-inducing dietary models of HCC. Disrupting PBRM1 expression in vivo and in vitro
showed no connection between PBRM1 expression status and its involvement in liver cancer 
initiation or liver cancer plasticity. 
RPS6KA3 is a kinase protein that acts as an effector and negative feedback regulator of 
RAS/MAPK pathway. The results from this dissertation demonstrated that RPS6KA3 loss 
contributes to tumorigenicity in vivo and that the loss of RPS6KA3 leads to an upregulation of 
the MAPK pathway both in vivo and in vitro with murine and human HCC cell lines. Moreover, 
RPS6KA3-depleted murine xenograft tumors and orthotopically transplanted human HCC cells 
lines with low RPS6KA3 levels responded remarkably to trametinib, a FDA-approved MEK 
inhibitor. Thus, the results not only reveal RPS6KA3 as an important tumor suppressor in HCC 
but also implicate RPS6KA3 as a novel biomarker for MAPK pathway inhibitors in HCC patients.
TI  - The role of tumor suppressor genes PBRM1 and RPS6KA3 in primary liver cancer
AV  - public
ER  -