Abstract：
The global pandemic of metabolic diseases has increased the incidence of hepatocellular carcinoma (HCC) in the context of non-alcoholic steatohepatitis (NASH). The downregulation of the E3 ubiquitin ligase TRIM21 has been linked to poor prognosis in different cancers including HCC. In order to investigate the role of TRIM21 in liver cancer progression on NASH, Trim21+/+ and Trim21-/- male mice were injected with streptozotocin at the neonatal stage. The hypoinsulinemic mice were then fed with a high-fat high-cholesterol diet (HFHCD) for 4, 8 or 12 weeks. All mice developed NASH which systematically resulted in HCC progression. Interestingly, compared to the Trim21+/+ control mice, liver damage was worsened in Trim21-/- mice, with more HCC nodules found after 12 weeks on HFHCD. Immune population analysis in the spleen and liver revealed a higher proportion of CD4+PD-1+ and CD8+PD-1+ T cells in Trim21-/- mice. The liver and HCC tumors of Trim21-/- mice also exhibited an increase in the number of PD-L1+ and CD68+ PD-L1+ cells. Thus, TRIM21 limits the emergence of HCC nodules in mice with NASH by potentially restricting the expression of PD-1 in lymphocytes and PD-L1 in tumors.
摘要：
在非酒精性脂肪性肝炎（NASH）的背景下，代谢性疾病的全球流行增加了肝细胞癌（HCC）的发病率。E3泛素连接酶TRIM21的下调与包括HCC在内的不同癌症的不良预后有关。为了研究TRIM21在NASH肝癌进展中的作用，Trim21+/+和Trim21-/-雄性小鼠在新生期注射链脲佐菌素。然后用高脂肪高胆固醇饮食(HFHCD)喂养低胰岛素血症小鼠4、8或12周。所有小鼠均发生NASH，系统性地导致HCC进展。有趣的是,与Trim21+/+对照小鼠相比，肝脏损伤在Trim21-/-小鼠中恶化，在HFHCD治疗12周后发现更多的HCC结节。脾脏和肝脏中的免疫群体分析显示Trim21-/-小鼠中CD4+PD-1+和CD8+PD-1+T细胞的比例更高。Trim21-/-小鼠的肝脏和HCC肿瘤也表现出PD-L1+和CD68+PD-L1+细胞数量的增加。因此，TRIM21通过潜在地限制肿瘤中淋巴细胞中PD-1和PD-L1的表达来限制NASH小鼠中HCC结节的出现。
