Identification of BXDC2 as a Key Downstream Effector of the Androgen Receptor in Modulating Cisplatin Sensitivity in Bladder Cancer.

Autor: Jiang G; Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.; Department of Pathology, China Medical University, Shenyang 110122, Liaoning Province, China., Teramoto Y; Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA., Goto T; Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA., Mizushima T; Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Inoue S; Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Ide H; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Nagata Y; Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA., Kashiwagi E; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Baras AS; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA., Netto GJ; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35249, USA., Yang Z; Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA., Miyamoto H; Department of Pathology & Laboratory Medicine, University of Rochester Medical Center, Rochester, NY 14642, USA.; James P. Wilmot Cancer Institute, University of Rochester Medical Center, Rochester, NY 14642, USA.; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.; Department of Urology, University of Rochester Medical Center, Rochester, NY 14642, USA.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2021 Feb 26; Vol. 13 (5). Date of Electronic Publication: 2021 Feb 26.
DOI: 10.3390/cancers13050975
Abstrakt: Underlying mechanisms for resistance to cisplatin-based chemotherapy in bladder cancer patients are largely unknown, although androgen receptor (AR) activity, as well as extracellular signal-regulated kinase (ERK) signaling, has been indicated to correlate with chemosensitivity. We also previously showed ERK activation by androgen treatment in AR-positive bladder cancer cells. Because our DNA microarray analysis in control vs. AR-knockdown bladder cancer lines identified BXDC2 as a potential downstream target of AR, we herein assessed its functional role in cisplatin sensitivity, using bladder cancer lines and surgical specimens. BXDC2 protein expression was considerably downregulated in AR-positive or cisplatin-resistant cells. BXDC2-knockdown sublines were significantly more resistant to cisplatin, compared with respective controls. Without cisplatin treatment, BXDC2-knockdown resulted in significant increases/decreases in cell proliferation/apoptosis, respectively. An ERK activator was also found to reduce BXDC2 expression. Immunohistochemistry showed downregulation of BXDC2 expression in tumor (vs. non-neoplastic urothelium), higher grade/stage tumor (vs. lower grade/stage), and AR-positive tumor (vs. AR-negative). Patients with BXDC2-positive/AR-negative muscle-invasive bladder cancer had a significantly lower risk of disease-specific mortality, compared to those with a BXDC2-negative/AR-positive tumor. Additionally, in those undergoing cisplatin-based chemotherapy, BXDC2 positivity alone ( p = 0.083) or together with AR negativity ( p = 0.047) was associated with favorable response. We identified BXDC2 as a key molecule in enhancing cisplatin sensitivity. AR-ERK activation may thus be associated with chemoresistance via downregulating BXDC2 expression in bladder cancer.
Databáze: MEDLINE
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