Abstract
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.
Highlights
Melanoma is the deadliest form of skin cancer
This, coupled with the fact that WM1552C cells were originally isolated from a primary melanoma lesion at the transition between radial growth phase (RGP) and vertical growth phase (VGP), provided us with a cell line to explore the effects of merlin expression on tumorigenicity
We found that merlin knockdown promoted post-confluence cell proliferation (Figure 1C), which is consistent with the reported role of merlin in maintenance of the contact inhibition of cell growth [14]
Summary
Melanoma is the deadliest form of skin cancer It is readily curable if diagnosed at an early stage, a large percentage of melanomas arise without association with premalignant nevi [1]. This leads to ineffective early detection and results in approximately ten percent of patients presenting with metastatic disease upon first diagnosis [2]. 50% of malignant melanomas harbor a BRAF activating mutation, the majority of these being BRAFV600E [7,8], which results in constitutive activation of BRAF and increased activation of the MAP kinase pathway. It is essential to identify additional signaling pathways and molecules that play critical roles in melanoma growth and progression, which could serve as the potential points of intervention for future therapies
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