Abstract
MX2 protein is a dynamin-like GTPase2 that has recently been identified as an interferon-induced restriction factor of HIV-1 and other primate lentiviruses. A single nucleotide polymorphism (SNP), rs45430, in an intron of the MX2 gene, was previously reported as a novel melanoma susceptibility locus in genome-wide association studies. Functionally, however, it is still unclear whether and how MX2 contributes to melanoma susceptibility and tumorigenesis. Here, we show that MX2 is differentially expressed in melanoma tumors and cell lines, with most metastatic cell lines showing lower MX2 expression than primary melanoma cell lines and melanocytes. Furthermore, high expression of MX2 RNA in primary melanoma tumors is associated with better patient survival. Overexpression of MX2 reduces in vivo proliferation partially through inhibition of AKT activation, suggesting that it can act as a tumor suppressor in melanoma. However, we have also identified a subset of melanoma cell lines with high endogenous MX2 expression where downregulation of MX2 leads to reduced proliferation. In these cells, MX2 downregulation interfered with DNA replication and cell cycle processes. Collectively, our data for the first time show that MX2 is functionally involved in the regulation of melanoma proliferation but that its function is context-dependent.
Highlights
Cutaneous melanoma makes up approximately 4% of skin cancers, yet it is responsible for more than 70% of skin cancer‐related deaths (Sample & He, 2018)
Complete lack of immunoreactivity was observed in 2.4% nevi, 7.8% primary, and 15% metastatic tumors, respectively, suggesting that MX2 is downregulated during disease progression in a proportion of tumors
MX2 has been mainly defined by its antiviral functions, high‐ lighting its induction by type I IFN and ability to interfere with the replication of different types of negative‐stranded RNA viruses
Summary
Cutaneous melanoma makes up approximately 4% of skin cancers, yet it is responsible for more than 70% of skin cancer‐related deaths (Sample & He, 2018). While MX1 protein is mainly induced after type I IFN (IFNα/β) stimulation during the antiviral response (Haller & Kochs, 2010; Kim, Shenoy, Kumar, Bradfield, & MacMicking, 2012), MX2 can be expressed at significant levels even in the absence of IFN (King, Raposo, & Lemmon, 2004). One previous study suggested that MX2 could have additional, viral‐independent cellular functions including regulation of cell cycle progression (King et al, 2004). We show for the first time, to best of our knowledge, that MX2 is functionally involved in cancer‐related processes in mela‐ noma. It is differentially expressed in melanoma tumors and cell lines, and it is a predictor of better patient survival. Our data further show that MX2 function is complex, with both tumor‐sup‐ pressive and oncogenic features depending on the cellular context
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
