Expression of natural killer cell regulatory microRNA by uveal melanoma cancer stem cells
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Natural killer (NK) cells are implicated in the control of metastasis in uveal melanoma, a process that has been ascribed to its cancer stem cell subpopulation. NK cell activation is regulated by specific microRNA (miR). The NK cell sensitivity and regulatory miR production of uveal melanoma cancer stem cells was examined. Cancer stem cells enriched from aggressively metastatic MUM2B uveal melanoma cells by selecting CD271+ cells or propagating as non-adherent spheres in stem-cell supportive were more resistant to NK cell cytolysis than cancer stem cells enriched from less aggressively metastatic OCM1 uveal melanoma cells. Both MUM2B and OCM1 cells expressed and secreted NK cell regulatory miRs, including miR 146a, 181a, 20a, and 223. MUM2B cells expressed and secreted miR-155; OCM1 cells did not. Transfecting MUM2B cells with anti-miR-155 increased NK cell sensitivity. CD271+ cells were identified in the blood of patients with metastatic uveal melanoma and were characterized by low expression of melanocyte differentiation determinants and by the ability to form non-adherent spheres in stem-cell supportive media. These cells also expressed NK cell regulatory miRs, including miR-155. These results indicate that uveal melanoma cancer stem cells can vary in their sensitivity to NK cell lysis and their expression of NK cell regulatory miRs. Circulating CD271+ cells from patients with metastatic uveal melanoma manifest cancer stem cell features and express miRs associated with NK cell suppression, including miR-155, that may contribute to metastatic progression.
KeywordsCD271 Melanospheres miR-155 Major histocompatibility complex class I molecules MHC class I-related chain A Microphthalmia-associated transcription factor
This work was supported in part by R21CA175671 from the National Cancer Institute, National Institutes of Health, Bethesda, MD.
Compliance with ethical standards
Conflict of interest
The authors declare that they do not have any competing or financial interests.
Blood samples were collected from patients with metastatic uveal melanoma and from normal subjects according to protocols approved by the Cleveland Clinic and Wake Forest University Institutional Review Boards. All subjects gave informed consent prior to inclusion in the study. This research was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments.
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