Therapeutic potential of tLyp-1-EV-shCTCF in inhibiting liver cancer stem cell self-renewal and immune escape via SALL3 modulation in hepatocellular carcinoma

•Sparse SALL3 expression in HCC foretells undesirable patient outcomes.•Boosting SALL3 impedes DNMT3A-facilitated mtDNA methylation and glycolytic adaptations.•CTCF favors H3K27me3 embellishments, constraining SALL3 output.•tLyp-1-EV-shCTCF's bolstering of SALL3 offsets metabolic drifts and LCS...

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Published in:Translational oncology Vol. 49; p. 102048
Main Authors: Zhu, Heng, Xie, Zhihui
Format: Journal Article
Language:English
Published: United States Elsevier Inc 01-11-2024
Neoplasia Press
Elsevier
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Summary:•Sparse SALL3 expression in HCC foretells undesirable patient outcomes.•Boosting SALL3 impedes DNMT3A-facilitated mtDNA methylation and glycolytic adaptations.•CTCF favors H3K27me3 embellishments, constraining SALL3 output.•tLyp-1-EV-shCTCF's bolstering of SALL3 offsets metabolic drifts and LCSC's proliferative drive.•Research insights pioneer groundbreaking HCC management and detection techniques. 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.
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ISSN:1936-5233
1936-5233
DOI:10.1016/j.tranon.2024.102048