Correlation of Sprouty1 and Jagged1 With Aggressive Prostate Cancer Cells With Different Sensitivities to Androgen Deprivation

Authors

  • Naoki Terada,

    1. Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Takumi Shiraishi,

    1. Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Yu Zeng,

    1. Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Koh-Meng Aw-Yong,

    1. Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Steven M. Mooney,

    1. Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Zhi Liu,

    1. Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Sayuri Takahashi,

    1. Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Jun Luo,

    1. Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Shawn E. Lupold,

    1. Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Prakash Kulkarni,

    1. Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
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  • Robert H. Getzenberg

    Corresponding author
    1. Departments of Urology, Oncology, Pharmacology and Molecular Sciences, James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland
    • Correspondence to: Robert H. Getzenberg, PhD, 175 Toyota Plaza, 7th Floor, Memphis, TN 38103.

      E-mail: rhgetzenberg@gmail.com

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  • Current address of Naoki Terada is Department of Urology, Kyoto University, Kyoto, Japan.
  • Current address of Yu Zeng is Department of Urology, The First Hospital of China Medical University, Shenyang, China.
  • Current address of Koh-Meng Aw-Yong is Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI.
  • Current address of Prakash Kulkarni is Institute for Bioscience & Biotechnology Research, University of Maryland, Rockville, MD.
  • Current address of Robert Getzenberg is GTx Inc., Memphis, TN.
  • Conflict of interest: None.

ABSTRACT

Prostate cancer is a heterogeneous disease and thus, it is important to understand whether among the heterogeneous collection of cell types, androgen-deprivation insensitive cells exist prior to hormonal manipulation. We established several LNCaP subclones with distinct insensitivities to androgen deprivation from a parental LNCaP cell line. In the resulting clones, the sensitivity to androgen-deprivation negatively correlated with their PSA expression levels. In two of these clones, an androgen insensitive clone, LNCaP-cl1, and an androgen sensitive clone, LNCaP-cl5, the DNA copy number differed significantly, indicating that these clones contain genetically distinct cells. LNCaP-cl1 had higher PSA expression but lower invasiveness and tumor growth potential than LNCaP-cl5. The expression levels of two genes that are known to be regulated by miR-21, an androgen-regulated microRNA, Sprouty1 (SPRY1) and Jagged1 (JAG1) were significantly lower in LNCaP-cl1 than in LNCaP-cl5. Knocking down SPRY1 in LNCaP cells enhanced PSA expression and cell proliferation. JAG1 administration in LNCaP cells enhanced cell invasion and JAG1 knockdown in PC3 cells suppressed cell invasion and tumor formation. These results indicated that the expression differences in SPRY1 and JAG1 may contribute to the phenotypic differences between the LNCaP-cl1 and LNCaP-cl5 clones. In tissue samples, SPRY1 expression levels were significantly lower in prostate cancer patients with PSA recurrence after surgical treatment (P = 0.0076) and JAG1 expression levels were significantly higher in Gleason sum (GS) 8–9 disease than in GS 5–6 (P = 0.0121). In summary a random population of LNCaP cells comprises a heterogeneous group of cells with different androgen-deprivation sensitivities and potential for invasiveness. J. Cell. Biochem. 115: 1505–1515, 2014. © 2014 Wiley Periodicals, Inc.

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