SIAH2 function as an oncogene in various cancer. However, the roles of SIAH2 in hepatocellular carcinoma (HCC) are still unknown. This study aimed to investigate the roles of SIAH2 in HCC. Immunohistochemistry was used determine SIAH2 and ACSL4 expression in clinical samples. RT-qPCR was used to determine mRNA expression. Western blot assay was applied for determining protein expression. Ubiquitination assay was conducted for determining ubiquitination of ACSL4. Xenograft experiment was applied for determining tumor growth. Flow cytometry was applied to determine the functions of CD4+ and CD8+ T cells. SIAH2 expression was overexpressed in HCC tumors. High levels of SIAH2 predicted poor outcomes. However, SIAH2 knockdown promoted the proliferation of CD8+ T cells as well as promoted the ferroptosis of tumor cells, inhibiting tumor growth in HCC. ACSL4 is required for CD8+ T cell-mediated ferroptosis of HCC cells. However, SIAH2 induced ubiquitination of ACSL4 and inhibited its expression. SIAH2 specific inhibitor menadione promoted the immune checkpoint blockade. Taken together, SIAH2-mediated inactivation of CD8+ T cells inhibits the ferroptosis of HCC via mediating ubiquitination of ACSL4. Therefore, targeting SIAH2 may be a promising strategy for HCC.

中文翻译：

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SIAH2 介导的 ACSL4 降解抑制肝细胞癌中 CD8+ T 细胞的抗肿瘤活性

SIAH2 在多种癌症中充当癌基因。然而，SIAH2在肝细胞癌（HCC）中的作用仍不清楚。本研究旨在探讨SIAH2在HCC中的作用。使用免疫组织化学测定临床样本中的 SIAH2 和 ACSL4 表达。 RT-qPCR 用于测定 mRNA 表达。应用蛋白质印迹法测定蛋白质表达。进行泛素化测定以确定 ACSL4 的泛素化。应用异种移植实验来确定肿瘤生长。应用流式细胞术测定CD4+和CD8+T细胞的功能。 SIAH2 在 HCC 肿瘤中过度表达。高水平的 SIAH2 预示着不良结果。然而，SIAH2敲低促进了CD8+T细胞的增殖，并促进了肿瘤细胞的铁死亡，抑制了HCC中的肿瘤生长。 ACSL4 是 CD8+ T 细胞介导的 HCC 细胞铁死亡所必需的。然而，SIAH2 诱导 ACSL4 泛素化并抑制其表达。 SIAH2特异性抑制剂甲萘醌促进免疫检查点阻断。总之，SIAH2 介导的 CD8+ T 细胞失活通过介导 ACSL4 泛素化抑制 HCC 铁死亡。因此，针对 SIAH2 可能是治疗 HCC 的一个有前途的策略。