Role of IAPs in prostate cancer progression: immunohistochemical study in normal and pathological (benign hyperplastic, prostatic intraepithelial neoplasia and cancer) human prostate

Abstract

Background: In this study was investigate IAPs in normal human prostate (NP), benign prostatic hyperplasia (BPH), prostatic intraepithelial neoplasia (PIN) and prostatic carcinoma (PC), and their involvement in apoptosis/proliferation via NF-kB (TNF-alpha, IL-1) stimulation.

Methods: Immunohistochemical and Western blot analyses were performed in 10 samples of normal prostates, 35 samples of BPH, 27 samples diagnosis of PIN (with low-grade PIN or high-grade PIN) and 95 samples of PC (with low, medium or high Gleason grades).

Results: In NP, cytoplasm of epithelial cells were positive to c-IAP1/2 (80% of samples), c-IAP-2 (60%), ILP (20%), XIAP (20%); negative to NAIP and survivin. In BPH, epithelial cells were immunostained to c-IAP1/2 (57.57%), c-IAP-2 (57.57%), ILP (66.6%), NAIP (60.6%), XIAP (27.27%), survivin (9.1%). Whereas low-grade PIN showed intermediate results between NP and BPH; results in high-grade PIN were similar to those found in PC. In PC, epithelial cells were immunostained to c-IAP1/2, c-IAP-2, ILP, NAIP, XIAP (no Gleason variation) and survivin (increasing with Gleason).

Conclusions: IAPs could be involved in prostate disorder (BPH, PIN and PC) development since might be provoke inhibition of apoptosis and subsequently cell proliferation. At the same time, different transduction pathway such as IL-1/NIK/NF-kB or TNF/NF-kB (NIK or p38) also promotes proliferation. Inhibitions of IAPs, IL-1alpha and TNFalpha might be a possible target for PC treatment since IAPs are the proteins that inhibited apoptosis (favour proliferation) and IL-1alpha and TNFalpha would affect all the transduction pathway involucrate in the activation of transcription factors related to survival or proliferation (NF-kB, Elk-1 or ATF-2).

Figure 1

Western blot analysis. Western blot analysis of c-IAP-1/2, c-IAP-2, ILP, NAIP, Survivin, XIAP and α-actin after 15% polyacrilamide gel electrophoresis. NP: normal prostate. BPH: benign prostate hyperplasia. PC: prostate carcinoma. The lanes showing a band correspond to a positively stained prostate of each group.

Figure 2

Immunohistochemical analysis. c-IAP-2 immunostaining appeared in the basal epithelial cells of normal (A) and BPH (B), whereas appeared in secretory epithelial cell of PC (C) samples. The cytoplasm of basal (normal and BPH) and secretory (cancer) epithelial cells presented positive immunoreaction to ILP in normal (D), high grade prostatic intraepithelial neoplasia (PIN) (E) and PC samples (F). No immunoreaction was found to NAIP in normal prostate (G) but was localized in the cytoplasm of epithelial cells in BPH (H) and PC (I) samples. Normal prostate (J) was negative to Survivin whereas immunoreaction was found in epithelial cells of BPH (K) and PC (L) samples. Immunoreaction to XIAP was observed in the apical cytoplasm of epithelial cells in BPH patients (Figs. M-N) whereas was perinuclear in high grade prostatic intraepithelial neoplasia (PIN) and PC (P) samples. Scale bars: 10 μm (O), 20 μm (B, E, H) and 30 μm (A, C-D, F-G, I-N, P).