Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/β-Catenin Signaling.
Merlin/NF2 Suppresses Pancreatic Tumor Growth and Metastasis by Attenuating the FOXM1-Mediated Wnt/β-Catenin Signaling.
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DOI：
10.1158/0008-5472.can-14-1952
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发表时间：
2015-11-15
期刊：
影响因子：
11.2
通讯作者：
Xie K
中科院分区：
文献类型：
--
作者：
Quan M;Cui J;Xia T;Jia Z;Xie D;Wei D;Huang S;Huang Q;Zheng S;Xie K
Merlin是由NF2基因编码的蛋白质，是细胞骨架相关蛋白质带4.1家族的成员，对许多类型的癌症具有肿瘤抑制作用。然而，Merlin在胰腺癌中的作用和机制尚不清楚。在这项研究中，我们试图利用人类组织标本、细胞系和动物模型来确定Merlin表达对胰腺癌发生和发展的影响。在人胰腺肿瘤和癌细胞系中，Merlin的表达明显降低。功能分析表明，Merlin基因的恢复表达抑制了胰腺肿瘤的生长和体内转移。此外，Merlin抑制Wnt/β-catenin信号转导下游基因的表达和β-catenin蛋白的核表达，Forkhead box M1(FOXM1)的过表达减弱了Merlin对Wnt/β-catenin信号转导的抑制作用。从机制上讲，Merlin降低了FOXM1蛋白的稳定性，而FOXM1蛋白在β-连环蛋白的核转位中起着关键作用。综上所述，这些发现表明，Merlin通过抑制FOXM1/β-catenin信号通路对胰腺癌的发生起关键作用，提示靶向新的Merlin/FOXM1/β-catenin信号通路是治疗胰腺癌的有效策略。
Merlin, the protein encoded by the NF2 gene, is a member of the band 4.1 familly of cytoskeleton-associated proteins and functions as a tumor suppressor for many types of cancer. However, the roles and mechanism of Merlin expression in pancreatic cancer have remained unclear. In this study, we sought to determine the impact of Merlin expression on pancreatic cancer development and progression using human tissue specimens, cell lines, and animal models. Decreased expression of Merlin was pronounced in human pancreatic tumors and cancer cell lines. Functional analysis revealed that restored expression of Merlin inhibited pancreatic tumor growth and metastasis in vitro and in vivo. Furthermore, Merlin suppressed the expression of Wnt/β-catenin signaling downstream genes and the nuclear expression of β-catenin protein, and overexpression of Forkhead box M1 (FOXM1) attenuated the suppressive effect of Merlin on Wnt/β-catenin signaling. Mechanistically, Merlin decreased the stability of FOXM1 protein, which plays critical roles in nuclear translocation of β-catenin. Collectively, these findings demonstrated that Merlin critically regulated pancreatic cancer pathogenesis by suppressing FOXM1/β-catenin signaling, suggesting that targeting novel Merlin/FOXM1/β-catenin signaling is an effective therapeutic strategy for pancreatic cancer.