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    Characterization of CD44 intracellular domain interaction with RUNX2 in PC3 human prostate cancer cells

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    Author
    Senbanjo, L.T.
    Aljohani, H.
    Majumdar, S.
    Chellaiah, M.A.
    Date
    2019
    Journal
    Cell Communication and Signaling
    Publisher
    BioMed Central Ltd.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://www.doi.org/10.1186/s12964-019-0395-6
    Abstract
    Background: Expression of CD44 receptor is associated with the onset of several tumors. The intracellular domain of CD44 (CD44-ICD) has been implicated as a co-transcription factor for RUNX2 in the regulation of expression of MMP-9 in breast carcinoma cells. Previous studies from our laboratory demonstrated the role of CD44 in migration and invasion of PC3 prostate cells through activation of MMP-9. CD44 signaling regulates the phosphorylation and hence the localization of RUNX2 in the nucleus. The role of CD44-ICD has not been studied in prostate cancer cells. This study aimed to explore the role of CD44-ICD and RUNX2 in the regulation of expression of metastasis-related genes. Methods: PC3 and PC3 cells overexpressing RUNX2 protein were analyzed for RUNX2/CD44-ICD interaction by immunoprecipitation, immunoblotting, and Immunofluorescence analyses. Wound healing and tumorsphere formation analyses were also done in these cells. The real-time PCR analysis was used to detect the expression levels of different genes. Results: Expression of CD44 and RUNX2 was observed only in PC3 cells (androgen receptor positive) and not in LNCaP or PCa2b cells (androgen receptor negative). Therefore, CD44-ICD fragment (~ 15-16 kDa) was observed in PC3 cells. Moreover, localization of CD44-ICD was more in the nucleus than in the cytoplasm of PC3 cells. Inhibition of cleavage of CD44 with a γ-secretase inhibitor, DAPT reduced the formation of CD44-ICD; however, accumulation of CD44-external truncation fragments (~ 20 and ~ 25 kDa) was detected. RUNX2 and CD44-ICD interact in the nucleus of PC3 cells, and this interaction was more in PC3 cells transfected with RUNX2 cDNA. Overexpression of RUNX2 augments the expression of metastasis-related genes (e.g., MMP-9 and osteopontin) which resulted in increased migration and tumorsphere formation. Conclusions: We have shown here a strong functional relationship between CD44-ICD and RUNX2 in PC3 cells. RUNX2 forms a complex with CD44-ICD as a co-transcriptional factor, and this complex formation not only activates the expression of metastasis-related genes but also contributes to migration and tumorsphere formation. Therefore, RUNX2 and CD44-ICD are potential targets for anti-cancer therapy, and attenuation of their interaction may validate the regulatory effects of these proteins on cancer migration and progression. Copyright 2019 The Author(s).
    Sponsors
    This work was supported by a research grant to MAC from the National Institute of Health National Institute of Arthritis and Musculoskeletal and Skin Diseases (5R01AR066044).
    Keyword
    CD44
    CD44-ICD
    Metastasis
    Migration
    MMP-9
    OPN
    Prostate cancer
    RUNX2
    Tumorigenesis
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85069771872&doi=10.1186%2fs12964-019-0395-6&partnerID=40&md5=2c17f68fe95b97221fefbaacea61a4ce; http://hdl.handle.net/10713/10368
    ae974a485f413a2113503eed53cd6c53
    10.1186/s12964-019-0395-6
    Scopus Count
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