Department of Strabismus and Pediatric Ophthalmology, the Second Hospital of Jilin University, Changchun, 130041, P. R. China.
Department of Orbital Disease and Ocular Plastic Surgery, the Second Hospital of Jilin University, No. 218, Ziqiang Street, Nanguan District, Changchun, Jilin Province, 130041, P. R. China.
Mol Med. 2023 Sep 14;29(1):126. doi: 10.1186/s10020-023-00713-7.
Tumor immune microenvironment regulates the growth and metastasis of uveal melanoma (UM). This study aims to reveal the possible molecular mechanism of BRCA1-associated protein 1 (BAP1) mutations in affecting the tumor immune microenvironment in UM through mediating the nuclear factor-κB (NF-κB) signaling pathway.
TCGA and cBioPortal databases jointly analyzed the genes with high mutation frequency in UM samples. Following survival analysis of UM patients, UM samples with BAP1 mutations were subjected to immune cell infiltration analysis. The signaling pathways associated with the mutated genes were screened by GSEA. Subsequently, the differential BAP1 expression was analyzed in the selected UM cell lines with wild type (WT) or mutant type (MUT) BAP1.
Bioinformatics analysis identified 12 genes mutated in the UM samples, while only BAP1 mutations were related to the prognosis of UM patients. UM patients with BAP1 mutations had higher immune cell infiltration. BAP1 mutations inhibited the NF-κB signaling pathway, suppressing the cytokine secretion and antigen presentation by macrophages. Rescue experiments confirmed that overexpressed NF-κB could reverse the effect of BAP1 mutations on the immunosuppressive microenvironment, thus suppressing the malignant phenotypes of UM cells.
BAP1 mutations may inhibit the NF-κB signaling pathway, repressing the cytokine secretion and antigen presentation by macrophages, which induces the immunosuppressive microenvironment, enhances the malignant phenotypes of UM cells and ultimately promotes the growth and metastasis of UM.
肿瘤免疫微环境调节葡萄膜黑色素瘤（UM）的生长和转移。本研究旨在通过介导核因子-κB（NF-κB）信号通路，揭示 BRCA1 相关蛋白 1（BAP1）突变影响 UM 肿瘤免疫微环境的可能分子机制。
TCGA 和 cBioPortal 数据库联合分析 UM 样本中高频突变的基因。对 UM 患者进行生存分析后，对 BAP1 突变的 UM 样本进行免疫细胞浸润分析。通过 GSEA 筛选与突变基因相关的信号通路。随后，分析选择的具有野生型（WT）或突变型（MUT）BAP1 的 UM 细胞系中 BAP1 的差异表达。
生物信息学分析鉴定出 12 个在 UM 样本中发生突变的基因，而只有 BAP1 突变与 UM 患者的预后相关。BAP1 突变的 UM 患者具有更高的免疫细胞浸润。BAP1 突变抑制 NF-κB 信号通路，抑制巨噬细胞分泌细胞因子和呈递抗原。挽救实验证实，过表达 NF-κB 可以逆转 BAP1 突变对免疫抑制微环境的影响，从而抑制 UM 细胞的恶性表型。
BAP1 突变可能抑制 NF-κB 信号通路，抑制巨噬细胞分泌细胞因子和呈递抗原，诱导免疫抑制微环境，增强 UM 细胞的恶性表型，最终促进 UM 的生长和转移。
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