A linker between Hippo and AKT pathways
Ablation of PTEN in mouse induces liver cancer via AKT activation. Similarly, Hippo pathway disruption also induces liver cancer via YAP/TAZ activation. Still, the role of crosstalk between Hippo-YAP/TAZ and PTEN-AKT pathways in liver tumorigenesis remains unclear.
In recently published work by researchers at KAIST in the Department of Biological Sciences, the loss of both PTEN and SAV1 (the component of Hippo pathway) wsa discovered to hyperactivate AKT via YAP/TAZ-dependent upregulation of insulin receptor substrate 2 (IRS2). This rapidly promotes the spontaneous appearance of non-alcoholic fatty liver disease (NAFLD), leading to liver cancer. Ablation of YAP/TAZ or activation of the Hippo pathway each rescues these phenotypes. High YAP/TAZ expression in human HCCs is also associated with high IRS2 and pAKT expression.
In addition, we found that AKT inhibitor MK-2206 treatment attenuates NAFLD development and tumorigenesis. Our findings suggest that Hippo signaling interacts with AKT signaling to prevent NAFLD and liver cancer.
Since NAFLD is a major risk factor for liver tumorigenesis, its prevention is an important clinical goal, but there are currently no effective therapies. With the increasing prevalence of obesity, it is estimated that 30% of the U.S. population have NAFLD, and 25% of NAFLD-diagnosed patients will develop non-alcoholic steatohepatitis (NASH). This prompts researchres to clarify the detailed mechanisms of liver disease progression by using animal model mimicking human liver disease phenotype.
Here, we generated liver-specific PTEN and SAV1 double-knockout (DKO) mice to investigate any potential crosstalk between the Hippo and AKT pathways in vivo. DKO mice had the accelerated progression of Pten-/- livers through the steps of NAFLD, NASH, cirrhosis, and cancer. Hyperactivated AKT of DKO mice liver was found to be the key molecule for developing the NAFLD, therefore, clinical trial phase II AKT inhibitor MK-2206 alleviated the development of NAFLD and liver cancer in the DKO mice.
Increased YAP/TAZ activity in DKO liver potentiated AKT activity through transcriptional induction of IRS2 which is upstream of AKT. This is confirmed by generating quadruple knockout mice (YAP, TAZ, PTEN and SAV1) had rescued the fatty liver phenotype; this validated that YAP/TAZ facilitated the NAFLD through upregulating IRS2-AKT signaling. Moreover, additional mouse models including the MST1 transgenic mouse crossing with PTEN KO mouse and the DKO mouse knocout of IRS2 by AAV-CRISPR-Cas9 showed the ameliorated progression of NAFLD and liver cancer via decreasing IRS2-AKT.
In human HCC patient samples, the researchers examined the hepatic expression of YAP, TAZ, and IRS2 and found the positive correlations between IRS2 and YAP or TAZ mRNA levels and protein levels. To further confirm their results in human, they collected Korean HCC patient specimens with associated NAFLD and its IHC intensities for TAZ, YAP, IRS2, and pAKT was higher than HCC samples without NAFLD.
Lim et al demonstrated the positive feedback loop linking YAP/TAZ with IRS2-AKT signaling in the development of NAFLD. Moreover, given that DKO mice develop NAFLD, NASH and liver cancer at an early age that resembles with the progression of human liver disease, the DKO mouse model is valuable for drug studies targeting AKT. This work was published in Journal of Clinical Investigation 2018 (3) on pages 1010–1025(https://www.jci.org/articles/view/95802).
* lab webpage : http://dlim.kaist.ac.kr