A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma.
A splicing variant of Merlin promotes metastasis in hepatocellular carcinoma.
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Merlin 的剪接变体促进肝细胞癌的转移。
DOI：
10.1038/ncomms9457
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发表时间：
2015-10-07
影响因子：
16.6
通讯作者：
Li Z
中科院分区：
文献类型：
--
作者：
Luo ZL;Cheng SQ;Shi J;Zhang HL;Zhang CZ;Chen HY;Qiu BJ;Tang L;Hu CL;Wang HY;Li Z
由肿瘤抑制基因Nf 2编码的Merlin在肿瘤发生和转移中起着至关重要的作用。然而，很少有人知道梅林剪接形式的功能的重要性。在这项研究中，我们发现Merlin在人肝细胞癌（HCC）中的水平较低，特别是在转移性肿瘤中，它与预后不良有关。令人惊讶的是，缺少外显子2、3和4的Merlin剪接变体（Δ2- 4 Merlin）在HCC和门静脉癌栓（PVTT）标本中以及在源自PVTT的CSQT 2细胞系中扩增。我们的研究表明，Δ2- 4 Merlin干扰野生型Merlin结合β-catenin和ERM的能力，并且它在细胞质中而不是在细胞表面表达。此外，Δ2- 4 Merlin过表达可增加β-catenin和干细胞相关基因的表达水平，诱导上皮-间充质转化表型，促进体外细胞迁移和体内肺转移的形成。我们的研究结果表明，Δ2- 4 Merlin变体破坏Merlin的正常功能并促进肿瘤转移。 Merlin在肝脏肿瘤发生中作为肿瘤抑制剂起着至关重要的作用。在这里，作者表明，缺失外显子2、3和4的Merlin剪接变体（Δ2- 4 Merlin）在肝癌中高度表达，并通过干扰野生型Merlin与β-连环蛋白的结合促进肿瘤转移。
Merlin, which is encoded by the tumour suppressor gene Nf2, plays a crucial role in tumorigenesis and metastasis. However, little is known about the functional importance of Merlin splicing forms. In this study, we show that Merlin is present at low levels in human hepatocellular carcinoma (HCC), particularly in metastatic tumours, where it is associated with a poor prognosis. Surprisingly, a splicing variant of Merlin that lacks exons 2, 3 and 4 (Δ2–4Merlin) is amplified in HCC and portal vein tumour thrombus (PVTT) specimens and in the CSQT2 cell line derived from PVTT. Our studies show that Δ2–4Merlin interferes with the capacity of wild-type Merlin to bind β-catenin and ERM, and it is expressed in the cytoplasm rather than at the cell surface. Furthermore, Δ2–4Merlin overexpression increases the expression levels of β-catenin and stemness-related genes, induces the epithelium–mesenchymal-transition phenotype promoting cell migration in vitro and the formation of lung metastasis in vivo. Our results indicate that the Δ2–4Merlin variant disrupts the normal function of Merlin and promotes tumour metastasis. Merlin plays a crucial role as a tumour suppressor in liver tumorigenesis. Here, the authors show that a splicing variant of Merlin that lacks exons 2,3 and 4 (Δ2–4Merlin) is highly expressed in hepatocarcinoma and promotes tumour metastasis by interfering with the binding of wild-type Merlin to ß-catenin.