PDF(Pubmed)
Abstract：
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.
摘要：
原发性肝癌是全球癌症相关死亡的第三大原因。越来越多的证据表明，在肝脏的生理和病理过程中，Hippo肿瘤抑制途径在限制细胞增殖和决定细胞命运中起着至关重要的作用。由NF2（2型神经纤维瘤病）基因编码的Merlin（Moesin-Ezrin-Radixin样蛋白）是Hippo信号通路的上游调节因子。Merlin靶向质膜似乎对其主要的肿瘤抑制功能至关重要;这通过与膜相关蛋白的相互作用来促进。包括CD44（分化簇44）。已经在许多人类癌症中报道了Merlin的CD44结合结构域内的突变。这项研究评估了CD44和Merlin依赖性过程对肝肿瘤发展和进展的相对贡献。为此,将具有肝脏特异性Nf2基因缺失的小鼠与Cd44敲除小鼠杂交，并进行广泛的组织学检查，生化和分子分析。此外,从突变肝脏中分离细胞并通过体外测定进行分析。肝脏中Nf2的缺失导致大量肝脏肿大和肝细胞癌（HCC）的产生，肝内胆管癌（ICCAs），以及混合型肝细胞胆管癌。虽然Cd44的缺失对肝脏大小或原发性肝肿瘤的发展没有影响，它显着抑制Nf2突变小鼠的转移形成。CD44上调整合素β2的表达并促进肝癌细胞的内皮迁移，这可能有助于转移扩散。总的来说,我们的结果表明,CD44可能是一个有希望的干预肝癌转移扩散的靶点.
