It has been reported that caveolin-1 (Cav-1) acts as a tumor promoter in hepatocellular carcinoma (HCC). Our previous studies showed that Cav-1 promoted mouse hepatocarcinoma cell adhesion to fibronectin by upregulating β-galactoside α2,6-sialyltransferase I (ST6Gal-I) expression. However, the detailed mechanism by which Cav-1 regulates ST6Gal-I is not fully understood. In this study, we found that the expression levels of Cav-1 and ST6Gal-I were increased in HCC tissues and correlated with poor prognosis. Cav-1 upregulated ST6Gal-I expression to promote the migration and invasion of HCC cells by inducing epithelial-to-mesenchymal transition. Importantly, the binding of the transcription factor nuclear receptor 4A2/retinoid X receptor alpha (NR4A2/RXRα) to the -550/-200 region of the ST6GAL1 promoter was critical for Cav-1-induced ST6GAL1 gene expression. Furthermore, Cav-1 expression activated the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling pathway, followed by upregulation of NR4A2 expression and phosphorylation of RXRα, which facilitated the complex of NR4A2 and phosphorylated RXRα forming and binding to the ST6GAL1 promoter region to induce its transcription. Finally, in the diethylnitrosamine (DEN)-induced HCC murine model, the expression levels of NR4A2, p-RXRα, ST6Gal-I, and α2,6-linked sialic acid decreased in parallel in Cav-1^−/− mice compared with Cav-1^+/+ mice, which was consistent with the above in vitro results. These findings provide insight into the mechanism of ST6GAL1 gene transcription mediated by Cav-1, which may lead to the development of novel therapeutic strategies targeting metastasis in HCC.

据报道，caveolin-1 (Cav-1) 在肝细胞癌 (HCC) 中充当肿瘤启动子。我们之前的研究表明，Cav-1 通过上调 β-半乳糖苷 α2,6-唾液酸转移酶 I (ST6Gal-I) 的表达来促进小鼠肝癌细胞对纤连蛋白的粘附。然而，Cav-1 调节 ST6Gal-I 的详细机制尚不完全清楚。在本研究中，我们发现 Cav-1 和 ST6Gal-I 在 HCC 组织中的表达水平增加，并与不良预后相关。Cav-1 上调 ST6Gal-I 表达，通过诱导上皮间质转化促进 HCC 细胞的迁移和侵袭。重要的是，转录因子核受体 4A2/维甲酸 X 受体 α (NR4A2/RXRα) 与 ST6GAL1 的 -550/-200 区域的结合启动子对 Cav-1 诱导的ST6GAL1基因表达至关重要。此外，Cav-1 表达激活了雷帕霉素 (PI3K/AKT/mTOR) 信号通路的磷脂酰肌醇 3-激酶/蛋白激酶 B/哺乳动物靶标，随后上调 NR4A2 表达和 RXRα 磷酸化，这促进了 NR4A2 和磷酸化的复合物。 RXRα 形成并与ST6GAL1启动子区域结合以诱导其转录。最后，在二乙基亚硝胺 (DEN) 诱导的 HCC 小鼠模型中，与Cav相比，Cav -1 ^-/-小鼠中 NR4A2、p-RXRα、ST6Gal-I 和 α2,6-连接的唾液酸的表达水平平行降低-1 ^+/+小鼠，与上述体外一致结果。这些发现提供了对Cav-1 介导的ST6GAL1基因转录机制的深入了解，这可能会导致开发针对 HCC 转移的新治疗策略。