Department of Medicine I, University Medical Center of the Johannes Gutenberg University, 55131 Mainz, Germany.
Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), 07745 Jena, Germany.
Cells. 2023 Apr 26;12(9):1257. doi: 10.3390/cells12091257.
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 (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 gene were crossed with -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 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 had no influence on liver size or primary liver tumor development, it significantly inhibited metastasis formation in -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.
原发性肝癌是全球癌症相关死亡的第三大主要原因。越来越多的证据表明，Hippo 肿瘤抑制途径在肝脏的生理和病理过程中对限制细胞增殖和决定细胞命运起着关键作用。由 （神经纤维瘤病 2 型）基因编码的 Merlin（Moesin-Ezrin-Radixin-like protein）是 Hippo 信号通路的上游调节剂。 Merlin 靶向质膜似乎对其主要的肿瘤抑制功能至关重要；这是通过与膜相关蛋白的相互作用来实现的，包括 CD44（分化群 44）。已经在许多人类癌症中报道了 Merlin 的 CD44 结合域内的突变。本研究评估了 CD44 和 Merlin 依赖过程对肝肿瘤发生和发展的相对贡献。为此，将肝脏特异性缺失 基因的小鼠与 -敲除小鼠杂交，并进行了广泛的组织学、生化和分子分析。此外，还从突变肝脏中分离细胞，并通过体外分析进行分析。肝脏中 基因的缺失导致肝肿大和肝细胞癌（HCC）、肝内胆管癌（iCCA）以及混合性肝细胞胆管癌的产生。虽然 基因缺失对肝大小或原发性肝癌的发展没有影响，但它显著抑制了 -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跨内皮迁移，这可能促进转移的扩散。总的来说，我们的结果表明 CD44 可能是干预肝癌转移扩散的有希望的靶点。
