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Gene expression profiling of effect of Yap inhibition in a genetically engineered mouse model of hepatocellular carcinoma

ABSTRACT: Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. We show that YAP functions as a rheostat maintaining metabolic specialization, differentiation and quiescence within the hepatocyte compartment. Importantly, treatment with siRNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model (mice with liver-specific Mst1/Mst2 double knockout). Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of positional identity of hepatocytes, supports targeting YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype potentially responsive to this approach.

ORGANISM(S): Mus musculus

PROVIDER: GSE65665 | GEO | 2015/03/07

SECONDARY ACCESSION(S): PRJNA274661

REPOSITORIES: GEO

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Gene expression profiling of effect of Yap inhibition in a genetically engineered mouse model of hepatocellular carcinoma

Project description:Defective Hippo/YAP signaling in the liver results in tissue overgrowth and development of hepatocellular carcinoma (HCC). Here, we uncover mechanisms of YAP-mediated hepatocyte reprogramming and HCC pathogenesis. We show that YAP functions as a rheostat maintaining metabolic specialization, differentiation and quiescence within the hepatocyte compartment. Importantly, treatment with siRNA-lipid nanoparticles (siRNA-LNPs) targeting YAP restores hepatocyte differentiation and causes pronounced tumor regression in a genetically engineered mouse HCC model (mice with liver-specific Mst1/Mst2 double knockout). Furthermore, YAP targets are enriched in an aggressive human HCC subtype characterized by a proliferative signature and absence of CTNNB1 mutations. Thus, our work reveals Hippo signaling as a key regulator of positional identity of hepatocytes, supports targeting YAP using siRNA-LNPs as a paradigm of differentiation-based therapy, and identifies an HCC subtype potentially responsive to this approach. Mice with liver-specific Mst1/Mst2 double-knockout (Adeno-Cre injected Mst1-/-; Mst2Flox/Flox mice) were monitored for the formation of HCC by ultrasound imaging. Animals were then randomized to be treated by intravenous injection of either siYap-LNPs or siLuciferase-LNPs for a period of 9 days.

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