Primary
liver cancer is the third leading cause of
cancer-related death worldwide. An increasing body of evidence suggests that the Hippo
tumor suppressor pathway plays a critical role in restricting cell proliferation and determining cell fate during physiological and
pathological processes in the liver.
Merlin (
Moesin-Ezrin-Radixin-like protein) encoded by the NF2 (
neurofibromatosis type 2) gene is an upstream regulator of the Hippo signaling pathway. Targeting of
Merlin to the plasma membrane seems to be crucial for its major
tumor-suppressive functions; this is facilitated by interactions with
membrane-associated proteins, including CD44 (cluster of differentiation 44). Mutations within the CD44-binding domain of
Merlin have been reported in many human
cancers. This study evaluated the relative contribution of CD44- and
Merlin-dependent processes to the development and progression of liver
tumors. To this end, mice with a liver-specific deletion of the Nf2 gene were crossed with Cd44-knockout mice and subjected to extensive histological, biochemical and molecular analyses. In addition, cells were isolated from mutant livers and analyzed by in vitro assays. Deletion of Nf2 in the liver led to substantial liver enlargement and generation of
hepatocellular carcinomas (HCCs),
intrahepatic cholangiocarcinomas (iCCAs), as well as mixed hepatocellular
cholangiocarcinomas. Whilst deletion of Cd44 had no influence on liver size or primary liver
tumor development, it significantly inhibited
metastasis formation in Nf2-mutant mice. CD44 upregulates expression of
integrin β2 and promotes transendothelial migration of
liver cancer cells, which may facilitate metastatic spreading. Overall, our results suggest that CD44 may be a promising target for intervening with metastatic spreading of
liver cancer.