Merlin is a negative regulator of human melanoma growth.
Merlin is a negative regulator of human melanoma growth.
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DOI：
10.1371/journal.pone.0043295
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Yu Q
中科院分区：
文献类型：
--
作者：
Murray LB;Lau YK;Yu Q
Merlin 由 2 型神经纤维瘤病 (NF2) 基因编码，是 Band 4.1 蛋白家族的成员。该蛋白质充当连接体，将细胞表面蛋白连接到肌动蛋白细胞骨架。 NF2基因突变引起的缺陷会引起NF2疾病，其一般特征是形成双侧前庭神经鞘瘤，以及较小程度的脑膜瘤和室管膜瘤。除了这些肿瘤类型之外，在许多非 NF2 相关肿瘤（包括黑色素瘤）中，NF2 发生突变和/或 merlin 表达减少或丢失。然而，merlin 在人类黑色素瘤生长中的作用及其作用机制目前尚不清楚。在本研究中，我们发现 merlin 敲低可增强体外黑色素瘤细胞的增殖、迁移和侵袭，并且 merlin 表达减少可促进免疫功能低下小鼠的皮下黑色素瘤生长。一致地，我们发现转移性黑色素瘤细胞系中 merlin 表达的增加减少了它们的体外迁移和增殖，并降低了它们以不依赖贴壁的方式生长的能力。 merlin 表达的增加也会抑制这些黑色素瘤细胞的体内生长。最后，我们证明人黑色素瘤细胞中较高的 merlin 水平可促进 H2O2 诱导的 MST1/2 Ser/Thr 激酶激活，MST1/2 Ser/Thr 激酶是 Hippo 信号通路中已知的肿瘤抑制因子。总而言之，这些结果首次提供了证据，证明 merlin 对人类黑色素瘤的生长具有负调节作用，而 merlin 的丧失或 merlin 功能受损会导致相反的效果。此外，我们发现 merlin 表达增加会导致 MTS1/2 激酶的激活增强，这意味着 MST1/2 在介导 merlin 的抗黑色素瘤作用中具有潜在作用。
Merlin is encoded by the neurofibromatosis type 2 (NF2) gene and is a member of the Band 4.1 protein family. This protein acts as a linker that connects cell surface proteins to the actin cytoskeleton. Defects caused by mutations of the NF2 gene give rise to NF2 disease, which is generally characterized by the formation of bilateral vestibular schwannomas and, to a lesser extent, meningiomas and ependymomas. In addition to these tumor types, NF2 is mutated and/or merlin expression is reduced or lost in numerous non-NF2 associated tumors, including melanoma. However, the role of merlin in human melanoma growth and the mechanism underlying its effect are currently unknown. In the present study, we show that merlin knockdown enhances melanoma cell proliferation, migration, and invasion in vitro and that decreased merlin expression promotes subcutaneous melanoma growth in immunocompromised mice. Concordantly, we find that increased expression of merlin in a metastatic melanoma cell line reduced their in vitro migration and proliferation, and diminished their ability to grow in an anchorage independent manner. Increased merlin expression also inhibits in vivo growth of these melanoma cells. Lastly, we demonstrate that higher merlin levels in human melanoma cells promote the H2O2-induced activation of MST1/2 Ser/Thr kinases, which are known tumor suppressors in the Hippo signaling pathway. Taken together, these results provide for the first time evidence that merlin negatively regulates human melanoma growth, and that loss of merlin, or impaired merlin function, results in an opposite effect. In addition, we show that increased merlin expression leads to enhanced activation of the MTS1/2 kinases, implying the potential roles of MST1/2 in mediating the anti-melanoma effects of merlin.
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影响因子：
30.8
作者：
BIANCHI, AB;HARA, T;KLEY, N
通讯作者：
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