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The interplay between AR, EGF receptor and MMP-9 signaling pathways in invasive prostate cancer
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
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2018 (English)In: Molecular medicine (Cambridge, Mass. Print), ISSN 1076-1551, E-ISSN 1528-3658, Vol. 24, p. 1-13, article id UNSP 34Article in journal (Refereed) Published
Abstract [en]

Background: Metastatic Prostate cancer (PCa) cells have gained survival and invasive advantages. Epidermal growth factor (EGA) receptor is a receptor tyrosine kinase, which may mediate signalling to promote progression and invasion of various cancers. In this study, we uncovered the molecular mechanisms underlying the interconnection among the androgen receptor (AR), matrix metalloproteinase-9 (MMP9) and EGFR in promoting PCa progression. Methods: Immunohistochemical analysis of the tissue microarrays consisting of primary and metastatic PCa tissues was performed. The clinical importance of EGFR and its association with survivals were analyzed using three cohorts from MSKCC Prostate Oncogenome Project dataset (For primary tumors, n = 181; for metastatic tumors n = 37) and The Cancer Genome Atlas Prostate Adenocarcinoma Provisional dataset (n = 495). Targeted overexpression or inhibition of the proteins of interests was introduced into PCa cell lines. Treatment of PCa cell lines with the compounds was conducted. Immunoblot analysis was performed. Results: We showed that AR, MMP-9 and EGFR are interconnect factors, which may cooperatively promote PCa progression. Altered EGFR expression was associated with poor disease-free survival in PCa patients. Induced overexpression of AR led to an increase in the expression of EGFR, p-GSK-313 and decrease in p27 expression in PCa cell lines in the presence of androgen stimulation. Overexpression of MMP9 significantly induced EGFR expression in PCa cells. Inhibition of PIP5K1a, a lipid kinase that acts upstream of PI3K/AKT greatly reduced expressions of AR, MMP-9 and EGFR. Conclusions: Our findings also suggest that PCa cells may utilize AR, EGFR and MMP-9 pathways in androgen-dependent as well as in castration-resistant conditions. Our data suggest a new therapeutic potential to block cancer metastasis by targeting AR, EGFR and MMP-9 pathways in subsets of PCa patients.

Place, publisher, year, edition, pages
Springer, 2018. Vol. 24, p. 1-13, article id UNSP 34
Keywords [en]
Prostate cancer, Cancer metastasis, Epidermal growth factor receptor, Androgen receptor and androgen
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Identifiers
URN: urn:nbn:se:umu:diva-150769DOI: 10.1186/s10020-018-0035-4ISI: 000437685200001PubMedID: 30134822OAI: oai:DiVA.org:umu-150769DiVA, id: diva2:1244388
Available from: 2018-08-31 Created: 2018-08-31 Last updated: 2018-08-31Bibliographically approved

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Semenas, JuliusPersson, Jenny L.

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Mandel, AnnaSemenas, JuliusPersson, Jenny L.
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