PTEN Deletion and Heme Oxygenase-1 Overexpression Are Associated with Adverse Clinical Outcome and Cooperate in Prostate Cancer Progression.
Yunru Li, Su Jack, Xiao DingZhang, Maisa Yoshimoto, Shuhong Liu, Krikor Bijian, Ajay Gupta, Jeremy A Squire, Jianguo Zhang, Moulay Alaoui Jamali, Tarek A Bismar. University of Calgary and Calgary Laboatory Services, AB, Canada; McGill University, Montreal, QC, Canada; Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China; Queen's University, Kingston, ON, Canada; University of Calgary, AB, Canada
Background: Over-expression of heme oxygenase-1 (HO-1), a sensor and regulator of oxidative stress and tissue redox homeostasis, and deletion of PTEN, a tumor suppressor gene, has been reported in prostate cancer (PCA).
Design: We assessed HO-1 expression and PTEN deletion, and their prognostic values, in two cohorts of men with localized PCA and castration resistant prostate cancer (CRPC). HO-1 expression was scored semi-quantitatively and PTEN status was assessed by a four-color interphase FISH.
Results: There was a significant difference between HO-1 epithelial expression between benign, high-grade prostatic intraepithelial neoplasia (HGPIN), localized PCA, and CRPC (p<0.0001). The highest epithelial HO-1 expression was noted in CRPC (2.00 ± 0.89) followed by benign prostate tissue (1.49 + 1.03), localized PCA (1.20 + 0.95) and HGPIN (1.07 + 0.87). PTEN deletions were observed in 66% and 42.6% of CRPC and localized PCA, respectively. Although neither HO-1 overexpression nor PTEN deletion by itself in localized PCA showed significant association with PSA relapse, the combined status of both markers correlated with disease progression (Log-rank test, p= 0.01). In preclinical prostate cancer model, inhibition of HO-1 by shRNA in PC3M cells where PTEN is restored, strongly reduced cell growth and invasion in-vitro and inhibited tumor growth and lung metastasis formation in mice compared to control cells or to where only HO-1 is inhibited or PTEN is restored.
Conclusions: We provide novel evidence for strong correlation between epithelial HO-1 expression and PTEN deletions in relation to PCA patient's outcome. This cooperation is supported by data using PCA preclinical model where both HO-1 and PTEN were manipulated. These findings open-up novel cooperative genetic pathways associated with PCA progression and could potentially lead to discovery of novel therapeutic modalities for advanced PCA.
Category: Genitourinary (including renal tumors)
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 98, Monday Morning