WNT5B promotes the malignant phenotype of non-small cell lung cancer via the FZD3-DVL3-RAC1-PCP-JNK pathway.

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  • Additional Information
    • Source:
      Publisher: Elsevier Science Ltd Country of Publication: England NLM ID: 8904683 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-3913 (Electronic) Linking ISSN: 08986568 NLM ISO Abbreviation: Cell Signal Subsets: MEDLINE
    • Publication Information:
      Publication: Oxford : Elsevier Science Ltd
      Original Publication: Oxford ; New York : Pergamon Press, 1988-
    • Subject Terms:
      Carcinoma, Non-Small-Cell Lung*/metabolism ; Carcinoma, Non-Small-Cell Lung*/pathology ; Carcinoma, Non-Small-Cell Lung*/genetics ; Frizzled Receptors*/metabolism ; rac1 GTP-Binding Protein*/metabolism ; Lung Neoplasms*/metabolism ; Lung Neoplasms*/pathology ; Lung Neoplasms*/genetics ; Dishevelled Proteins*/metabolism ; Wnt Proteins*/metabolism; Humans ; Cell Line, Tumor ; Female ; Male ; Animals ; Cell Polarity ; Middle Aged ; Phenotype ; Mice, Nude ; MAP Kinase Signaling System ; Mice ; Wnt Signaling Pathway
    • Abstract:
      The WNT5B ligand regulates the non-canonical wingless-related integration site (WNT)-planar cell polarity (PCP) pathway. However, the detailed mechanism underlying the activity of WNT5B in the WNT-PCP pathway in non-small cell lung cancer (NSCLC) is unclear. In this study, we assessed the clinicopathological significance of WNT5B expression in NSCLC specimens. WNT5B-overexpression and -knockdown NSCLC cell lines were generated in vivo and in vitro, respectively. WNT5B overexpression in NSCLC specimens correlates with advanced tumor node metastasis (TNM) stage, lymph node metastasis, and poor prognosis in patients with NSCLC. Additionally, WNT5B promotes the malignant phenotype of NSCLC cells in vivo and in vitro. Interactions were identified among WNT5B, frizzled3 (FZD3), and disheveled3 (DVL3) in NSCLC cells, leading to the activation of WNT-PCP signaling. The FZD3 receptor initiates DVL3 recruitment to the membrane for phosphorylation in a WNT5B ligand-dependent manner and activates c-Jun N-terminal kinase (JNK) signaling via the small GTPase RAC1. Furthermore, the deletion of the DEP domain of DVL3 abrogated these effects. Overall, we demonstrated a novel signal transduction pathway in which WNT5B recruits DVL3 to the membrane via its DEP domain through interaction with FZD3 to promote RAC1-PCP-JNK signaling, providing a potential target for clinical intervention in NSCLC treatment.
      Competing Interests: Declaration of competing interest None.
      (Copyright © 2024. Published by Elsevier Inc.)
    • Contributed Indexing:
      Keywords: RAC1; WNT5B; c-Jun N-terminal kinase; disheveled3; frizzled3; non-small cell lung cancer
    • Accession Number:
      0 (Frizzled Receptors)
      EC 3.6.5.2 (rac1 GTP-Binding Protein)
      0 (Dishevelled Proteins)
      0 (DVL3 protein, human)
      0 (WNT5B protein, human)
      0 (FZD3 protein, human)
      0 (RAC1 protein, human)
      0 (Wnt Proteins)
    • Publication Date:
      Date Created: 20240802 Date Completed: 20240826 Latest Revision: 20240831
    • Publication Date:
      20240901
    • Accession Number:
      10.1016/j.cellsig.2024.111330
    • Accession Number:
      39094673