Medical School, Southeast University, Nanjing, 210009, China.
Hepatopancreatobiliary Center, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, 210009, China.
Apoptosis. 2024 Jun;29(5-6):898-919. doi: 10.1007/s10495-024-01938-5. Epub 2024 Feb 27.
The cytosolic sulfotransferases (SULTs) are phase II conjugating enzymes, which are widely expressed in the liver and mainly mediate the sulfation of numerous xenobiotics and endogenous compounds. However, the role of various SULTs genes has not been reported in hepatocellular carcinoma (HCC). This study aims to analyze the expression and potential functional roles of SULTs genes in HCC and to identify the role of SULT2A1 in HCC stemness as well as the possible mechanism. We found that all of the 12 SULTs genes were differentially expressed in HCC. Moreover, clinicopathological features and survival rates were also investigated. Multivariate regression analysis showed that SULT2A1 and SULT1C2 could be used as independent prognostic factors in HCC. SULT1C4, SULT1E1, and SULT2A1 were significantly associated with immune infiltration. SULT2A1 deficiency in HCC promoted chemotherapy resistance and stemness maintenance. Mechanistically, silencing of SULT2A1 activated the AKT signaling pathway, on the one hand, promoted the expression of downstream stemness gene c-Myc, on the other hand, facilitated the NRF2 expression to reduce the accumulation of ROS, and jointly increased HCC stemness. Moreover, knockdown NR1I3 was involved in the transcriptional regulation of SULT2A1 in stemness maintenance. In addition, SULT2A1 knockdown HCC cells promoted the proliferation and activation of hepatic stellate cells (HSCs), thereby exerting a potential stroma remodeling effect. Our study revealed the expression and role of SULTs genes in HCC and identified the contribution of SULT2A1 to the initiation and progression of HCC.
细胞质硫转移酶（SULTs）是Ⅱ相结合酶，广泛表达于肝脏，主要介导许多外源物和内源性化合物的磺化作用。然而，各种 SULTs 基因在肝细胞癌（HCC）中的作用尚未见报道。本研究旨在分析 SULTs 基因在 HCC 中的表达及潜在功能作用，并鉴定 SULT2A1 在 HCC 干性中的作用及其可能的机制。我们发现，12 种 SULTs 基因在 HCC 中均有差异表达。此外，还对临床病理特征和生存率进行了研究。多变量回归分析表明，SULT2A1 和 SULT1C2 可作为 HCC 的独立预后因素。SULT1C4、SULT1E1 和 SULT2A1 与免疫浸润显著相关。SULT2A1 在 HCC 中的缺失促进了化疗耐药和干性维持。机制上，沉默 SULT2A1 一方面激活 AKT 信号通路，促进下游干性基因 c-Myc 的表达，另一方面促进 NRF2 的表达以减少 ROS 的积累，共同增加 HCC 的干性。此外，NR1I3 的敲低参与了干性维持中 SULT2A1 的转录调控。此外，SULT2A1 敲低 HCC 细胞促进了肝星状细胞（HSCs）的增殖和激活，从而发挥潜在的基质重塑作用。本研究揭示了 SULTs 基因在 HCC 中的表达和作用，并确定了 SULT2A1 对 HCC 起始和进展的贡献。
