Knockdown of TGF-β in Pancreatic Cancer Helps Ameliorate Gemcitabine Resistance.

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  • Additional Information
    • Source:
      Publisher: IMR Press Country of Publication: Singapore NLM ID: 101612996 Publication Model: Print Cited Medium: Internet ISSN: 2768-6698 (Electronic) Linking ISSN: 27686698 NLM ISO Abbreviation: Front Biosci (Landmark Ed) Subsets: MEDLINE
    • Publication Information:
      Publication: 2022- : Singapore : IMR Press
      Original Publication: Searington, NY : Frontiers in Bioscience
    • Subject Terms:
      Gemcitabine* ; Deoxycytidine*/analogs & derivatives ; Deoxycytidine*/pharmacology ; Deoxycytidine*/therapeutic use ; Drug Resistance, Neoplasm*/genetics ; Drug Resistance, Neoplasm*/drug effects ; Pancreatic Neoplasms*/genetics ; Pancreatic Neoplasms*/metabolism ; Pancreatic Neoplasms*/drug therapy ; Pancreatic Neoplasms*/pathology ; Transforming Growth Factor beta*/metabolism ; Mice, Nude* ; Apoptosis*/drug effects ; Kruppel-Like Factor 4* ; Antimetabolites, Antineoplastic*/pharmacology ; Cell Proliferation*/drug effects ; Zinc Finger E-box-Binding Homeobox 1*/genetics ; Zinc Finger E-box-Binding Homeobox 1*/metabolism ; Gene Knockdown Techniques*; Animals ; Humans ; Cell Line, Tumor ; Mice ; Kruppel-Like Transcription Factors/genetics ; Kruppel-Like Transcription Factors/metabolism ; DNA-Binding Proteins/genetics ; DNA-Binding Proteins/metabolism ; Xenograft Model Antitumor Assays ; Transcription Factors/genetics ; Transcription Factors/metabolism
    • Abstract:
      Background: The TGF-β gene is a gemcitabine (GEM) resistance gene; however, the mechanism by which it regulates GEM resistance in pancreatic cancer remains unclear.
      Methods: The PANC-1 cell line was treated with GEM and then stimulated with TGF-β . Subsequently, we constructed GEM-resistant pancreatic cancer cell lines, knocked down TGF-β in these cell lines, and detected changes in the proliferation and apoptosis of drug-resistant cancer cells. In addition, the protein expression levels of KLF-4 , GFI-1 , and ZEB-1 were determined. The xenograft tumor models of nude mice were constructed by subcutaneously injecting GEM-resistant PANC-1 cells into mouse axilla. The tumors were removed, dissected, and weighed after 6 weeks. The protein levels of KLF-4 , GFI-1 , and ZEB-1 in tumor tissues were quantified. In addition, the percentage of M2 macrophages in tumor tissues was determined using flow cytometry.
      Results: The protein levels of TGF-β in pancreatic cancer cells were significantly decreased after GEM treatment. The protein expression of KLF-4 was downregulated, whereas the expressions of GFI-1 and ZEB-1 were upregulated after TGF-β stimulation. Apoptosis increased and proliferation decreased after TGF-β knockdown in GEM-resistant pancreatic cancer cells, moreover, silencing TGF-β promoted the expression of Caspase 3 and Cleaved caspase 3. In addition, the protein expression of KLF-4 was upregulated, whereas the expressions of GFI-1 and ZEB-1 were downregulated. Further, the volume and weight of the transplanted tumor decreased after TGF-β knockdown. The protein expression of KLF-4 was upregulated, whereas the expressions of GFI-1 and ZEB-1 were downregulated in tumor tissues. In addition, the percentage of M2 macrophages decreased in tumor tissues after TGF-β knockdown.
      Conclusions: The knockdown of TGF-β inhibits epithelial-to-mesenchymal transition, suppresses the proliferation and promotes the apoptosis of drug-resistant cancer cells, and decreases the macrophage polarization to the M2 phenotype, consequently ameliorating GEM resistance in pancreatic cancer.
      Competing Interests: The authors declare no conflict of interest.
      (© 2024 The Author(s). Published by IMR Press.)
    • Grant Information:
      CXPJJH12000001-2020304 Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province; 2021-ZJ-719 Foundation research project of Qinghai province
    • Contributed Indexing:
      Keywords: EMT; M2-type polarization; TGF-β; gemcitabine resistance; pancreatic cancer
    • Accession Number:
      0 (Gemcitabine)
      0W860991D6 (Deoxycytidine)
      0 (Transforming Growth Factor beta)
      0 (Kruppel-Like Factor 4)
      0 (Antimetabolites, Antineoplastic)
      0 (Zinc Finger E-box-Binding Homeobox 1)
      0 (Klf4 protein, mouse)
      0 (KLF4 protein, human)
      0 (Kruppel-Like Transcription Factors)
      0 (DNA-Binding Proteins)
      0 (ZEB1 protein, human)
      0 (Transcription Factors)
      0 (GFI1 protein, human)
    • Publication Date:
      Date Created: 20240731 Date Completed: 20240731 Latest Revision: 20240731
    • Publication Date:
      20240731
    • Accession Number:
      10.31083/j.fbl2907269
    • Accession Number:
      39082329