ArticleCellular and molecular gastroenterology and hepatology2023
Activation of Sphingomyelin Phosphodiesterase 3 in Liver Regeneration Impedes the Progression of Colorectal Cancer Liver Metastasis Via Exosome-Bound Intercellular Transfer of Ceramides.
Article in Cellular and molecular gastroenterology and hepatology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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8 citing papers in PubMed, 10 citations in OpenAlex.
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- Bioinformatic validation and machine learning based exploration of B cells-related gene signatures in the context of strategies for precision therapy to acute myeloid leukemia.Genes & diseases · 2026Article
- Extracellular vesicles cargo orchestration in colorectal cancer: immune evasion, stromal remodeling, and therapeutic frontiers.Molecular cancer · 2025Review
- SMPD3 as a Potential Biomarker and Therapeutic Target in Hepatocellular Carcinoma.International journal of genomics · 2025Article
- HIF-1α knockdown suppresses breast cancer metastasis via epithelial mesenchymal transition Abrogation.Heliyon · 2024Article
- Clinical Efficacy of Transcatheter Arterial Chemoembolization Combined With Percutaneous Microwave Coagulation Therapy for Advanced Hepatocellular Carcinoma.Gastroenterology research · 2024Article
- Altered lipid metabolism as a predisposing factor for liver metastasis in MASLD.Molecules and cells · 2024Review
- Novel Role for Ceramides in Colorectal Cancer Liver Metastases.Cellular and molecular gastroenterology and hepatology · 2023Article
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24 authors at 2 institutions in 1 country.
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No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND &
aimsThe machinery that prevents colorectal cancer liver metastasis (CRLM) in the context of liver regeneration (LR) remains elusive. Ceramide (CER) is a potent anti-cancer lipid involved in intercellular interaction. Here, we investigated the role of CER metabolism in mediating the interaction between hepatocytes and metastatic colorectal cancer (CRC) cells to regulate CRLM in the context of LR.
methodsMice were intrasplenically injected with CRC cells. LR was induced by 2/3 partial hepatectomy (PH) to mimic the CRLM in the context of LR. The alteration of corresponding CER-metabolizing genes was examined. The biological roles of CER metabolism in vitro and in vivo were examined by performing a series of functional experiments.
resultsInduction of LR augmented apoptosis but promoted matrix metalloproteinase 2 (MMP2) expression and epithelial-mesenchymal transition (EMT) to increase the invasiveness of metastatic CRC cells, resulting in aggressive CRLM. Up-regulation of sphingomyelin phosphodiesterase 3 (SMPD3) was determined in the regenerating hepatocytes after LR induction and persisted in the CRLM-adjacent hepatocytes after CRLM formation. Hepatic Smpd3 knockdown was found to further promote CRLM in the context of LR by abolishing mitochondrial apoptosis and augmenting the invasiveness in metastatic CRC cells by up-regulating MMP2 and EMT through promoting the nuclear translocation of β-catenin. Mechanistically, we found that hepatic SMPD3 controlled the generation of exosomal CER in the regenerating hepatocytes and the CRLM-adjacent hepatocytes. The SMPD3-produced exosomal CER critically conducted the intercellular transfer of CER from the hepatocytes to metastatic CRC cells and impeded CRLM by inducing mitochondrial apoptosis and restricting the invasiveness in metastatic CRC cells. The administration of nanoliposomal CER was found to suppress CRLM in the context of LR substantially.
conclusionsSMPD3-produced exosomal CER constitutes a critical anti-CRLM mechanism in LR to impede CRLM, offering the promise of using CER as a therapeutic agent to prevent the recurrence of CRLM after PH.
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