Downregulation of GPX8 in hepatocellular carcinoma: impact on tumor stemness and migration.

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  • Additional Information
    • Source:
      Publisher: Springer Country of Publication: Netherlands NLM ID: 101552938 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2211-3436 (Electronic) Linking ISSN: 22113428 NLM ISO Abbreviation: Cell Oncol (Dordr) Subsets: MEDLINE
    • Publication Information:
      Original Publication: Dordrecht : Springer
    • Subject Terms:
      Carcinoma, Hepatocellular*/genetics ; Carcinoma, Hepatocellular*/pathology ; Carcinoma, Hepatocellular*/metabolism ; Cell Movement*/genetics ; Down-Regulation*/genetics ; Gene Expression Regulation, Neoplastic* ; Liver Neoplasms*/genetics ; Liver Neoplasms*/pathology ; Liver Neoplasms*/metabolism ; Neoplastic Stem Cells*/metabolism ; Neoplastic Stem Cells*/pathology ; Signal Transduction*/genetics; Animals ; Female ; Humans ; Male ; Mice ; Middle Aged ; Cell Line, Tumor ; Glutathione Peroxidase/metabolism ; Glutathione Peroxidase/genetics ; Kruppel-Like Factor 4 ; Mice, Inbred BALB C ; Mice, Nude ; Proto-Oncogene Proteins c-akt/metabolism
    • Abstract:
      Purpose: GPX8, which is found in the endoplasmic reticulum lumen, is a member of the Glutathione Peroxidases (GPXs) family. Its role in hepatocellular carcinoma (HCC) is unknown.
      Methods: Immunohistochemical staining was used to detect the protein levels of GPX8 in HCC tissue microarrays. A short hairpin RNA lentivirus was used to knock down GPX8, and the main signaling pathways were investigated using transcriptome sequencing and a phosphorylated kinase array. The sphere formation assays, cloning-formation assays and cell migration assays were used to evaluate the stemness and migration ability of HCC cells. Identifying the GPX8-interacting proteins was accomplished through immunoprecipitation and protein mass spectrometry.
      Results: The GPX8 protein levels were downregulated in HCC patients. Low expression of GPX8 protein was related to early recurrence and poor prognosis in HCC patients. GPX8 knockdown could enhance the stemness and migration ability of HCC cells. Consistently, Based on transcriptome analysis, multiple signaling pathways that include the PI3K-AKT and signaling pathways that regulate the pluripotency of stem cells, were activated after GPX8 knockdown. The downregulation of GPX8 could increase the expression of the tumor stemness markers KLF4, OCT4, and CD133. The in vivo downregulation of GPX8 could also promote the subcutaneous tumor-forming and migration ability of HCC cells. MK-2206, which is a small-molecule inhibitor of AKT, could reverse the tumor-promoting effects both in vivo and in vitro. We discovered that GPX8 and the 71-kDa heat shock cognate protein (Hsc70) have a direct interaction. The phosphorylation of AKT encouraged the translocation of Hsc70 into the nucleus and the expression of the PI3K p110 subunit, thereby increasing the downregulation of GPX8.
      Conclusion: The findings from this study demonstrate the anticancer activity of GPX8 in HCC by inactivating the Hsc70/AKT pathway. The results suggest a possible therapeutic target for HCC.
      (© 2024. The Author(s).)
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    • Grant Information:
      82073217 National Natural Science Foundation of China; 2018SHZDZX05 Shanghai Municipal Science and Technology Major Project; 2019-I2M-5-058 Shanghai Municipal Key Clinical Specialty. CAMS Innovation Fund for Medical Sciences (CIFMS); 2018YFC1312100 National Key R&D Program of China; No. SHDC2020CR5007 Clinical Research Plan of SHDC; 202040221 Shanghai Municipal Health Commission
    • Contributed Indexing:
      Keywords: GPX8; Hepatocellular carcinoma; Hsc70; Migration; Tumor stemness
    • Accession Number:
      EC 1.11.1.9 (Glutathione Peroxidase)
      0 (KLF4 protein, human)
      0 (Kruppel-Like Factor 4)
      EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
      EC 1.11.1.- (GPX8 protein, human)
    • Publication Date:
      Date Created: 20240412 Date Completed: 20240813 Latest Revision: 20240925
    • Publication Date:
      20240925
    • Accession Number:
      PMC11322209
    • Accession Number:
      10.1007/s13402-024-00934-w
    • Accession Number:
      38607517