Upregulation of SLC12A3 and SLC12A9 Mediated by the HCP5/miR-140-5p Axis Confers Aggressiveness and Unfavorable Prognosis in Uveal Melanoma

Abstract

Perturbation of solute carriers (SLCs) has been implicated in metabolic disorders and cancer, highlighting the potential for drug discovery and therapeutic opportunities. However, there is relatively little exploration of the clinical relevance and potential molecular mechanisms underlying the role of the SLC12 family in uveal melanoma (UVM). Here, we performed an integrative multiomics analysis of the SLC12 family in multicenter UVM datasets and found that high expression of SLC12A3 and SLC12A9 was associated with unfavorable prognosis. Moreover, SLC12A3 and SLC12A9 were highly expressed in UVM in vivo. We experimentally characterized the roles of these proteins in tumorigenesis in vitro and explored their association with the prognosis of UVM. Lastly, we identified the HCP5-miR-140-5p axis as a potential noncoding RNA pathway upstream of SLC12A3 and SLC12A9, which was associated with immunomodulation and may represent a novel predictor for clinical prognosis and responsiveness to checkpoint blockade immunotherapy. These findings may facilitate a better understanding of the SLCome and guide future rationalized development of SLC-targeted therapy and drug discovery for UVM.

Keywords: T cell immunity; immunotherapy; solute carriers; uveal melanoma.