Apoptosis incidence and protein expression of p53, TGF-beta receptor II, p27Kip1, and Smad4 in benign, premalignant, and malignant human prostate.
Deregulation of apoptosis is involved in prostate cancer development and progression. This study involved an immunohistochemical "profiling" of prostate tissue specimens from patients who underwent prostatectomy for localized prostate cancer, to identify apoptosis-specific alterations associated with premalignant precursor lesions. Prostate tissue was pathologically evaluated, and areas of benign acini, high-grade prostate intraepithelial neoplasia (HGPIN), and prostate cancer were identified. Immunohistochemical analysis was performed to determine the expression of p27Kip1, a key cell cycle regulator, transforming growth factor (TGF)-beta receptor II (TbetaRII), a critical signaling effector of TGF-beta; Smad4, a downstream intracellular effector of TGF-beta signaling; p53, a key apoptosis regulator; and prostate-specific antigen (PSA), a clinical marker of prostate cancer. The apoptotic index of the same cell populations was determined using the transferase-mediated digoxigenin-tagged 16-desoxy-uridine-triphosphate nick end labeling assay. Our findings indicate a significant reduction in p27Kip1 immunoreactivity in HGPIN (P<0.0001) and prostate cancer (P<0.0001) compared with the benign tissue. A significant down-regulation was detected in TbetaRII expression in HGPIN and prostate cancer compared with benign prostatic hyperplasia (BPH)(P<0.001). A significant decrease was also observed in Smad4 levels in HGPIN and prostate cancer compared with BPH (P<0.001). Evaluation of the incidence of apoptosis revealed a significant decrease in the apoptotic index among the epithelial cell populations in HGPIN and a further decrease in prostate carcinoma (P<0.01). This reduced apoptotic index correlated with a significant increase in p53 immunoreactivity in the prostatic carcinoma foci. Prostate cancer cells exhibited strong nuclear staining for p53 compared with adjacent HGPIN (P<0.05) and the benign lesions of the same prostate specimens (P<0.05). A significant reduction in PSA immunostaining was detected in HGPIN and prostate carcinoma foci compared with the benign glandular epithelia (P<0.001). These results further define deregulation of TGF-beta signaling effectors as a molecular basis for loss of apoptotic control contributing to the development of prostate tumors. Identification of apoptotic regulators in precursor premalignant lesions may have prognostic significance in disease progression as well as therapeutic value for targeting prostate cancer.
Zeng
Li
L
Division of Urology, Department of Surgery, Lexington, KY 40536, USA.
Rowland
Randall G
RG
Lele
Subodh M
SM
Kyprianou
Natasha
N
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000378:metabolism; D002452:Cell Count; D018797:Cell Cycle Proteins / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27; D004268:DNA-Binding Proteins / Q000378:metabolism; D019084:Fluorescent Antibody Technique, Indirect; D006801:Humans; D007124:Immunoenzyme Techniques; D020287:In Situ Nick-End Labeling; D008297:Male; D008875:Middle Aged; D009363:Neoplasm Proteins / Q000378:metabolism*; D011470:Prostatic Hyperplasia / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D019048:Prostatic Intraepithelial Neoplasia / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000601:surgery; D051901:Smad4 Protein; D015534:Trans-Activators / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27