Tumor necrosis factor-α-induced protein 8 (TNFAIP8) expression has been linked to tumor progression in various cancer types, but the detailed mechanisms of TNFAIP8 are not fully elucidated. Here we define the role of TNFAIP8 in early events associated with development of hepatocellular carcinoma (HCC). Increased TNFAIP8 levels in HCC cells enhanced cell survival by blocking apoptosis, rendering HCC cells more resistant to the anticancer drugs, sorafenib and regorafenib. TNFAIP8 also induced autophagy and steatosis in liver cancer cells. Consistent with these observations, TNFAIP8 blocked AKT/mTOR signaling and showed direct interaction with ATG3-ATG7 proteins. TNFAIP8 also exhibited binding with fatty acids and modulated expression of lipid/fatty-acid metabolizing enzymes. Chronic feeding of mice with alcohol increased hepatic levels of TNFAIP8, autophagy, and steatosis but not in high-fat-fed obese mice. Similarly, higher TNFAIP8 expression was associated with steatotic livers of human patients with a history of alcohol use but not in steatotic patients with no history of alcohol use. Our data indicate a novel role of TNFAIP8 in modulation of drug resistance, autophagy, and hepatic steatosis, all key early events in HCC progression.

肿瘤坏死因子-α诱导的蛋白 8 (TNFAIP8) 表达与各种癌症类型的肿瘤进展有关，但 TNFAIP8 的详细机制尚未完全阐明。在这里，我们定义了 TNFAIP8 在与肝细胞癌 (HCC) 发展相关的早期事件中的作用。HCC 细胞中 TNFAIP8 水平的增加通过阻断细胞凋亡来增强细胞存活，使 HCC 细胞对抗癌药物索拉非尼和瑞戈非尼更具抗性。TNFAIP8 还在肝癌细胞中诱导自噬和脂肪变性。与这些观察结果一致，TNFAIP8 阻断 AKT/mTOR 信号传导并显示与 ATG3-ATG7 蛋白的直接相互作用。TNFAIP8 还表现出与脂肪酸的结合并调节脂质/脂肪酸代谢酶的表达。长期用酒精喂养小鼠会增加肝脏中 TNFAIP8 的水平，自噬和脂肪变性，但在高脂喂养的肥胖小鼠中没有。同样，较高的 TNFAIP8 表达与有饮酒史的人类患者的脂肪肝相关，但与没有饮酒史的脂肪肝患者无关。我们的数据表明 TNFAIP8 在调节耐药性、自噬和肝脂肪变性中的新作用，这些都是 HCC 进展的关键早期事件。