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SUMOylation of annexin A6 retards cell migration and tumor growth by suppressing RHOU/AKT1-involved EMT in hepatocellular carcinoma.

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  • معلومة اضافية
    • المصدر:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101170464 Publication Model: Electronic Cited Medium: Internet ISSN: 1478-811X (Electronic) Linking ISSN: 1478811X NLM ISO Abbreviation: Cell Commun Signal Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: [London] : BioMed Central, c2003-
    • الموضوع:
      Carcinoma, Hepatocellular*/pathology ; Liver Neoplasms*/pathology; Animals ; Humans ; Mice ; Annexin A6/genetics ; Annexin A6/metabolism ; Cell Line, Tumor ; Cell Movement/genetics ; Cell Proliferation ; Chromatography, Liquid ; Epithelial-Mesenchymal Transition/genetics ; Gene Expression Regulation, Neoplastic ; Proto-Oncogene Proteins c-akt/metabolism ; rho GTP-Binding Proteins/metabolism ; Sumoylation ; Tandem Mass Spectrometry
    • نبذة مختصرة :
      Background: The protein annexin A6 (AnxA6) is involved in numerous membrane-related biological processes including cell migration and invasion by interacting with other proteins. The dysfunction of AnxA6, including protein expression abundance change and imbalance of post-translational modification, is tightly related to multiple cancers. Herein we focus on the biological function of AnxA6 SUMOylation in hepatocellular carcinoma (HCC) progression.
      Methods: The modification sites of AnxA6 SUMOylation were identified by LC-MS/MS and amino acid site mutation. AnxA6 expression was assessed by immunohistochemistry and immunofluorescence. HCC cells were induced into the epithelial-mesenchymal transition (EMT)-featured cells by 100 ng/mL 12-O-tetradecanoylphorbol-13-acetate exposure. The ability of cell migration was evaluated under AnxA6 overexpression by transwell assay. The SUMO1 modified AnxA6 proteins were enriched from total cellular proteins by immunoprecipitation with anti-SUMO1 antibody, then the SUMOylated AnxA6 was detected by Western blot using anti-AnxA6 antibody. The nude mouse xenograft and orthotopic hepatoma models were established to determine HCC growth and tumorigenicity in vivo. The HCC patient's overall survival versus AnxA6 expression level was evaluated by the Kaplan-Meier method.
      Results: Lys579 is a major SUMO1 modification site of AnxA6 in HCC cells, and SUMOylation protects AnxA6 from degradation via the ubiquitin-proteasome pathway. Compared to the wild-type AnxA6, its SUMO site mutant AnxA6 K579R leads to disassociation of the binding of AnxA6 with RHOU, subsequently RHOU-mediated p-AKT1 ser473 is upregulated to facilitate cell migration and EMT progression in HCC. Moreover, the SENP1 deSUMOylates AnxA6, and AnxA6 expression is negatively correlated with SENP1 protein expression level in HCC tissues, and a high gene expression ratio of ANXA6/SENP1 indicates a poor overall survival of patients.
      Conclusions: AnxA6 deSUMOylation contributes to HCC progression and EMT phenotype, and the combination of AnxA6 and SENP1 is a better tumor biomarker for diagnosis of HCC grade malignancy and prognosis.
      (© 2024. The Author(s).)
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    • Grant Information:
      31961143005 the International Cooperation Program of National Natural Sciences Foundation of China; 2020-GH02-00056-HZ Chengdu Science and Technology Program
    • Contributed Indexing:
      Keywords: (de)SUMOylation; Annexin A6; Cell migration; Epithelial-mesenchymal transition; Hepatocellular carcinoma
    • الرقم المعرف:
      EC 2.7.11.1 (AKT1 protein, human)
      0 (Annexin A6)
      EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
      EC 3.6.5.2 (rho GTP-Binding Proteins)
      EC 3.6.1.- (RHOU protein, human)
      0 (ANXA6 protein, human)
    • الموضوع:
      Date Created: 20240402 Date Completed: 20240404 Latest Revision: 20240406
    • الموضوع:
      20240406
    • الرقم المعرف:
      PMC10986105
    • الرقم المعرف:
      10.1186/s12964-024-01573-2
    • الرقم المعرف:
      38566133