tLyp-1-EV-shCTCF 通过 SALL3 调节抑制肝细胞癌干细胞自我更新和免疫逃逸的治疗潜力。
Therapeutic potential of tLyp-1-EV-shCTCF in inhibiting liver cancer stem cell self-renewal and immune escape via SALL3 modulation in hepatocellular carcinoma.
发表日期:2024 Aug 25
作者:
Heng Zhu, Zhihui Xie
来源:
Cellular & Molecular Immunology
摘要:
肝细胞癌 (HCC) 的进展受到代谢过程破坏的影响,这对预后结果提出了挑战。肝细胞癌 (HCC) 是癌症相关死亡的主要原因,与肝癌干细胞 (LCSC) 的代谢重编程和干细胞样特性密切相关。本研究探讨了 tLyP-1 修饰的细胞外囊泡 (EV) 传递 CTCF shRNA (tLyp-1-EV-shCTCF) 调节线粒体 DNA 甲基化诱导的糖酵解代谢重编程和 LCSC 自我更新的潜在分子机制。通过蛋白质印迹、纳米粒子追踪分析和免疫荧光等一系列方法,我们证明了 tLyp-1-EV 在 HCC 细胞中的成功递送和内化。我们的结果确定 SALL3 是 HCC 和 LCSC 中表达不足的关键因子,而 CTCF 则过表达。 SALL3的过度表达通过阻断CTCF-DNMT3A相互作用来抑制LCSC自我更新和免疫逃避,从而抑制DNMT3A甲基转移酶活性和随后的线粒体DNA甲基化介导的糖酵解代谢重编程。体内实验进一步支持了这些发现,表明 tLyp-1-EV-shCTCF 治疗通过上调 SALL3 表达显着减少肿瘤生长,从而抑制糖酵解代谢重编程并增强针对 HCC 细胞的免疫反应。这项研究为 SALL3 和线粒体 DNA 甲基化在 HCC 进展中的作用提供了新的见解,为对抗 HCC 及其干细胞样特性提供了潜在的治疗靶点。版权所有 © 2024。由 Elsevier Inc. 出版。
The progression of hepatocellular carcinoma (HCC) is influenced by disrupted metabolic processes, presenting challenges in prognostic outcomes. Hepatocellular carcinoma (HCC), a leading cause of cancer-related mortality, is closely associated with metabolic reprogramming and stem cell-like properties in liver cancer stem cells (LCSCs). This study explored the potential molecular mechanisms by which tLyP-1-modified extracellular vesicles (EVs) delivering CTCF shRNA (tLyp-1-EV-shCTCF) regulate mitochondrial DNA methylation-induced glycolytic metabolic reprogramming and LCSC self-renewal. Through a series of methods, including Western blot, nanoparticle tracking analysis, and immunofluorescence, we demonstrated the successful delivery and internalization of tLyp-1-EV in HCC cells. Our results identified SALL3 as a critical factor underexpressed in HCC and LCSCs, while CTCF was overexpressed. Overexpression of SALL3 inhibited LCSC self-renewal and immune evasion by blocking the CTCF-DNMT3A interaction, thus repressing DNMT3A methyltransferase activity and subsequent mitochondrial DNA methylation-mediated glycolytic metabolic reprogramming. In vivo experiments further supported these findings, showing that tLyp-1-EV-shCTCF treatment significantly reduced tumor growth by upregulating SALL3 expression, thereby inhibiting glycolytic metabolic reprogramming and enhancing the immune response against HCC cells. This study provides novel insights into the role of SALL3 and mitochondrial DNA methylation in HCC progression, offering potential therapeutic targets for combating HCC and its stem cell-like properties.Copyright © 2024. Published by Elsevier Inc.