{"title":"TREM2是热蛋白沉积的关键激活因子,它通过caspase 3/GSDME途径介导皮脂单酚对葡萄膜黑色素瘤细胞的抗肿瘤作用TREM2是热蛋白沉积的关键激活因子,它通过caspase 3/GSDME途径介导皮脂单酚对葡萄膜黑色素瘤细胞的抗肿瘤作用。","authors":"Xudong Jiu, Wenjie Li, Yang Liu, Lin Liu, Hong Lu","doi":"10.3892/ijmm.2024.5420","DOIUrl":null,"url":null,"abstract":"<p><p>Uveal melanoma (UM) is the most prevalent type of primary intraocular malignancy and is prone to metastasize, particularly to the liver. However, due to the poor understanding of the pathogenesis of UM, effective therapeutic approaches are lacking. As a phenolic compound extracted from grapes, piceatannol (PIC) exhibits anti‑cancer properties. To the best of our knowledge, however, the effects of PIC on UM have not been well investigated. Therefore, in the present study, considering the impact of pyroptosis on modulating cell viability, the mechanism underlying the effects of PIC on UM cell proliferation was explored. The inhibitory effect of PIC on proliferation of UM cells was detected by cell counting kit‑8 assay. Wound healing was used to investigate the effects of PIC on the migration of UM cells. Activity detecting assays were performed to test the apoptosis and oxidant level in UM cells. Western blotting and RT‑qPCR were used to detect the inflammatory and pyroptotic levels of UM cell after PIC treatment. PIC‑treated UM cells were screened by high‑throughput sequencing to detect the differential expression of RNA and differential genes. Si‑TREM2 transfection was used to verify the important role of TREM2 in the effects of PIC. Immunohistochemical staining was used to observe the expressions of TREM2 and GSDMR of tumor in nude mice after PIC administration. PIC effectively inhibited proliferation ability of C918 and Mum‑2b UM cell lines via enhancing apoptosis, as evidenced by enhanced activities of caspase 3 and caspase 9. In addition, treatment of UM cells with PIC attenuated cell migration in a dose‑dependent manner. PIC increased reactive oxygen species levels and suppressed the activity of the antioxidant enzymes superoxide dismutase, glutathione‑S‑transferase, glutathione peroxidase and catalase. PIC inhibited inflammatory responses in C918 cells. PIC treatment upregulated IL‑1β, IL‑18 and Nod‑like receptor protein 3 and downregulated gasdermin D (GSDMD). RNA sequencing results revealed the activation of an unconventional pyroptosis‑associated signaling pathway, namely caspase 3/GSDME signaling, following PIC treatment, which was mediated by triggering receptor expressed on myeloid cells 2 (TREM2) upregulation. As an agonist of TREM2, COG1410‑mediated TREM2 upregulation inhibited proliferation of C918 cells, displaying similar effects to PIC. Furthermore, PIC inhibited tumor growth via regulating the TREM2/caspase 3/GSDME pathway in a mouse model. Collectively, the present study revealed a novel mechanism underlying the inhibitory effects of PIC on UM, providing a potential treatment approach for UM in clinic.</p>","PeriodicalId":14086,"journal":{"name":"International journal of molecular medicine","volume":"54 5","pages":""},"PeriodicalIF":5.7000,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11410308/pdf/","citationCount":"0","resultStr":"{\"title\":\"TREM2, a critical activator of pyroptosis, mediates the anti‑tumor effects of piceatannol in uveal melanoma cells via caspase 3/GSDME pathway\",\"authors\":\"Xudong Jiu, Wenjie Li, Yang Liu, Lin Liu, Hong Lu\",\"doi\":\"10.3892/ijmm.2024.5420\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Uveal melanoma (UM) is the most prevalent type of primary intraocular malignancy and is prone to metastasize, particularly to the liver. However, due to the poor understanding of the pathogenesis of UM, effective therapeutic approaches are lacking. As a phenolic compound extracted from grapes, piceatannol (PIC) exhibits anti‑cancer properties. To the best of our knowledge, however, the effects of PIC on UM have not been well investigated. Therefore, in the present study, considering the impact of pyroptosis on modulating cell viability, the mechanism underlying the effects of PIC on UM cell proliferation was explored. The inhibitory effect of PIC on proliferation of UM cells was detected by cell counting kit‑8 assay. Wound healing was used to investigate the effects of PIC on the migration of UM cells. Activity detecting assays were performed to test the apoptosis and oxidant level in UM cells. Western blotting and RT‑qPCR were used to detect the inflammatory and pyroptotic levels of UM cell after PIC treatment. PIC‑treated UM cells were screened by high‑throughput sequencing to detect the differential expression of RNA and differential genes. Si‑TREM2 transfection was used to verify the important role of TREM2 in the effects of PIC. Immunohistochemical staining was used to observe the expressions of TREM2 and GSDMR of tumor in nude mice after PIC administration. PIC effectively inhibited proliferation ability of C918 and Mum‑2b UM cell lines via enhancing apoptosis, as evidenced by enhanced activities of caspase 3 and caspase 9. In addition, treatment of UM cells with PIC attenuated cell migration in a dose‑dependent manner. PIC increased reactive oxygen species levels and suppressed the activity of the antioxidant enzymes superoxide dismutase, glutathione‑S‑transferase, glutathione peroxidase and catalase. PIC inhibited inflammatory responses in C918 cells. PIC treatment upregulated IL‑1β, IL‑18 and Nod‑like receptor protein 3 and downregulated gasdermin D (GSDMD). RNA sequencing results revealed the activation of an unconventional pyroptosis‑associated signaling pathway, namely caspase 3/GSDME signaling, following PIC treatment, which was mediated by triggering receptor expressed on myeloid cells 2 (TREM2) upregulation. As an agonist of TREM2, COG1410‑mediated TREM2 upregulation inhibited proliferation of C918 cells, displaying similar effects to PIC. Furthermore, PIC inhibited tumor growth via regulating the TREM2/caspase 3/GSDME pathway in a mouse model. Collectively, the present study revealed a novel mechanism underlying the inhibitory effects of PIC on UM, providing a potential treatment approach for UM in clinic.</p>\",\"PeriodicalId\":14086,\"journal\":{\"name\":\"International journal of molecular medicine\",\"volume\":\"54 5\",\"pages\":\"\"},\"PeriodicalIF\":5.7000,\"publicationDate\":\"2024-11-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11410308/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"International journal of molecular medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.3892/ijmm.2024.5420\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/9/2 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"International journal of molecular medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.3892/ijmm.2024.5420","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/9/2 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
摘要
葡萄膜黑色素瘤(UM)是眼内原发性恶性肿瘤中最常见的一种,容易发生转移,尤其是向肝脏转移。然而,由于人们对葡萄膜黑色素瘤的发病机制了解甚少,因此缺乏有效的治疗方法。作为一种从葡萄中提取的酚类化合物,皮脂单酚(PIC)具有抗癌特性。然而,据我们所知,PIC 对 UM 的影响尚未得到很好的研究。因此,在本研究中,考虑到热渗透对调节细胞活力的影响,我们探讨了 PIC 对 UM 细胞增殖的影响机制。通过细胞计数试剂盒-8 检测 PIC 对 UM 细胞增殖的抑制作用。利用伤口愈合来研究 PIC 对 UM 细胞迁移的影响。活性检测试验用于检测 UM 细胞的凋亡和氧化水平。用 Western 印迹法和 RT-qPCR 检测 PIC 处理后 UM 细胞的炎症和裂解水平。通过高通量测序筛选经 PIC 处理的 UM 细胞,以检测 RNA 和差异基因的差异表达。用 Si-TREM2 转染验证 TREM2 在 PIC 作用中的重要作用。免疫组化染色观察了 PIC 给药后裸鼠肿瘤中 TREM2 和 GSDMR 的表达。PIC 通过增强细胞凋亡,有效抑制了 C918 和 Mum-2b UM 细胞株的增殖能力,表现为 caspase 3 和 caspase 9 活性的增强。此外,用 PIC 处理 UM 细胞还能以剂量依赖的方式减少细胞迁移。PIC 增加了活性氧水平,抑制了超氧化物歧化酶、谷胱甘肽-S-转移酶、谷胱甘肽过氧化物酶和过氧化氢酶等抗氧化酶的活性。PIC 可抑制 C918 细胞的炎症反应。PIC 处理可上调 IL-1β、IL-18 和 Nod 样受体蛋白 3,下调 gasdermin D (GSDMD)。RNA 测序结果显示,PIC 处理后激活了一个非常规的与化脓相关的信号通路,即 caspase 3/GSDME 信号通路,该通路由触发髓系细胞上表达的受体 2(TREM2)上调介导。作为 TREM2 的激动剂,COG1410 介导的 TREM2 上调抑制了 C918 细胞的增殖,其效果与 PIC 相似。此外,在小鼠模型中,PIC 通过调节 TREM2/caspase 3/GSDME 通路抑制肿瘤生长。总之,本研究揭示了 PIC 抑制 UM 的新机制,为临床治疗 UM 提供了一种潜在的方法。
TREM2, a critical activator of pyroptosis, mediates the anti‑tumor effects of piceatannol in uveal melanoma cells via caspase 3/GSDME pathway
Uveal melanoma (UM) is the most prevalent type of primary intraocular malignancy and is prone to metastasize, particularly to the liver. However, due to the poor understanding of the pathogenesis of UM, effective therapeutic approaches are lacking. As a phenolic compound extracted from grapes, piceatannol (PIC) exhibits anti‑cancer properties. To the best of our knowledge, however, the effects of PIC on UM have not been well investigated. Therefore, in the present study, considering the impact of pyroptosis on modulating cell viability, the mechanism underlying the effects of PIC on UM cell proliferation was explored. The inhibitory effect of PIC on proliferation of UM cells was detected by cell counting kit‑8 assay. Wound healing was used to investigate the effects of PIC on the migration of UM cells. Activity detecting assays were performed to test the apoptosis and oxidant level in UM cells. Western blotting and RT‑qPCR were used to detect the inflammatory and pyroptotic levels of UM cell after PIC treatment. PIC‑treated UM cells were screened by high‑throughput sequencing to detect the differential expression of RNA and differential genes. Si‑TREM2 transfection was used to verify the important role of TREM2 in the effects of PIC. Immunohistochemical staining was used to observe the expressions of TREM2 and GSDMR of tumor in nude mice after PIC administration. PIC effectively inhibited proliferation ability of C918 and Mum‑2b UM cell lines via enhancing apoptosis, as evidenced by enhanced activities of caspase 3 and caspase 9. In addition, treatment of UM cells with PIC attenuated cell migration in a dose‑dependent manner. PIC increased reactive oxygen species levels and suppressed the activity of the antioxidant enzymes superoxide dismutase, glutathione‑S‑transferase, glutathione peroxidase and catalase. PIC inhibited inflammatory responses in C918 cells. PIC treatment upregulated IL‑1β, IL‑18 and Nod‑like receptor protein 3 and downregulated gasdermin D (GSDMD). RNA sequencing results revealed the activation of an unconventional pyroptosis‑associated signaling pathway, namely caspase 3/GSDME signaling, following PIC treatment, which was mediated by triggering receptor expressed on myeloid cells 2 (TREM2) upregulation. As an agonist of TREM2, COG1410‑mediated TREM2 upregulation inhibited proliferation of C918 cells, displaying similar effects to PIC. Furthermore, PIC inhibited tumor growth via regulating the TREM2/caspase 3/GSDME pathway in a mouse model. Collectively, the present study revealed a novel mechanism underlying the inhibitory effects of PIC on UM, providing a potential treatment approach for UM in clinic.
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