溶质转运蛋白（SLCs）的扰动已被认为与代谢性疾病和癌症有关，突显了药物发现和治疗机会的潜力。但是，研究SLC12家族在葡萄膜黑色素瘤（UVM）中的作用的临床相关性和潜在分子机制的探索相对较少。本研究在多中心UVM数据集中进行了一种集成的多组学分析，并发现高表达SLC12A3和SLC12A9与不良预后相关。而且，在体内UVM中，SLC12A3和SLC12A9的表达很高。我们在体外实验中表征了这些蛋白在肿瘤发生中的作用，并探讨了它们与UVM预后的关联。最后，我们确定了HCP5-miR-140-5p轴作为SLC12A3和SLC12A9上游的潜在非编码RNA途径，这与免疫调节相关，可能代表一种新的临床预后及对检查点阻断免疫治疗的反应性的预测因子。这些发现可能有助于更好地理解SLC组和指导未来SLC靶向治疗和药物发现的合理开发，用于治疗UVM。版权所有©2022美国和加拿大病理学院。由Elsevier Inc.出版。保留所有权利。

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.Copyright © 2022 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.