Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, 710061, China.
Department of Gastroenterology, First Affiliated Hospital of Xi'an Jiaotong University, Shaanxi, 710061, China.
Biochem Biophys Res Commun. 2023 Feb 26;646:19-29. doi: 10.1016/j.bbrc.2022.12.076. Epub 2022 Dec 29.
There is a trend of increasing young cases with gastric cancer globally. Sensitive early diagnosis methods and new therapeutic approaches are still the focus of clinical diagnosis and therapy of gastric cancer. USP14 plays an extensive role in tumor malignancy and fat metabolism regulation. However, researchers still have gaps in their knowledge of its substrates, which makes it difficult for deubiquitinases to become clinical targets. TAMs were isolated from tumor or polarized from primary THP1 cells by tumors cell lines under the control of IU1 and FAO inhibitor therapy. Cytokines controlled macrophages were compared to evaluate the capability to induce USP14 expression. Fatty acid uptake assay and OCR measurement were used to analyze macrophage metabolism. USP14 is found the correlation with tumor poor prognosis and poor immunophenotype in gastric cancer patients and mouse tumor models. Activation of USP14 determines elevated protein stability of SIRT1 and is required for activation of macrophage fatty acid oxidation and immunosuppressive phenotype. Although overexpression of USP14 is not sufficient to polarize macrophages to the M2 phenotype, inhibition of USP14 by IU1 in tumor-bearing mice disrupts the suppressive activity of cancer-promoting macrophages and effectively reshapes immune microenvironment characteristics. Our study provides evidence that a novel therapeutic strategy that targets to lipid metabolism of macrophages in tumors could be a potential option for emerging treatments for gastric cancer.
全球范围内胃癌的年轻病例呈上升趋势。敏感的早期诊断方法和新的治疗方法仍然是胃癌临床诊断和治疗的重点。USP14 在肿瘤恶性和脂肪代谢调节中发挥广泛作用。然而，研究人员对其底物的了解仍存在差距，这使得去泛素化酶难以成为临床靶点。TAMs 是从肿瘤中分离出来的，或在肿瘤细胞系的控制下从原代 THP1 细胞中极化而来，用 IU1 和 FAO 抑制剂治疗。比较细胞因子控制的巨噬细胞，以评估诱导 USP14 表达的能力。脂肪酸摄取测定和 OCR 测量用于分析巨噬细胞代谢。在胃癌患者和小鼠肿瘤模型中发现 USP14 与肿瘤预后不良和免疫表型不良相关。USP14 的激活决定了 SIRT1 蛋白稳定性的升高，并且对于激活巨噬细胞脂肪酸氧化和免疫抑制表型是必需的。尽管 USP14 的过表达不足以将巨噬细胞极化为 M2 表型，但在荷瘤小鼠中用 IU1 抑制 USP14 会破坏促进癌症的巨噬细胞的抑制活性，并有效地重塑免疫微环境特征。我们的研究提供了证据，表明靶向肿瘤中巨噬细胞脂质代谢的新治疗策略可能是治疗胃癌的一种潜在选择。
