Local growth hormone promotes benign prostatic hyperplasia
Masaki Ryuzaki, Svetlana Zonis, Neil A. Bhowmick, Sandrine Billet, Saravana Kumar Kailasam Mani, Stephen J. Freedland, Hyung L. Kim, Vera Chesnokova, Shlomo Melmed
Masaki Ryuzaki, Svetlana Zonis, Neil A. Bhowmick, Sandrine Billet, Saravana Kumar Kailasam Mani, Stephen J. Freedland, Hyung L. Kim, Vera Chesnokova, Shlomo Melmed
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Research Article Aging Endocrinology

Local growth hormone promotes benign prostatic hyperplasia

Abstract

Locally produced nonpituitary growth hormone (npGH) promotes DNA damage accumulation and epithelial-mesenchymal transition (EMT) in aging human colon epithelium. GH receptor (GHR) and npGH are expressed in normal human prostate, and benign prostatic hyperplasia (BPH) prevalence increases with age. We hypothesized that local prostate GH action may promote EMT and contribute to BPH pathogenesis. We show here that the number of patients expressing npGH increases more than 10-fold after age 60, concordant with increased γH2AX, a marker of DNA damage, and EMT activation. GH-treated human primary prostate epithelial cells, normal prostate cells, and primary cell cultures derived from resected BPH specimens exhibited enhanced DNA damage and activated EMT, with induced TWIST2, suppressed E-cadherin, and increased Ki67, cell motility, and proliferation. In mice, prostate tissue adjacent to allografted GH-expressing fibroblasts showed increased γH2AX, TWIST2, and Ki67, along with morphological changes consistent with BPH. While GH and GH-induced IGF-1 both activated EMT, GH triggered DNA damage independently of IGF-1. These results elucidate what we believe to be a novel role for local npGH in aging prostate tissue, whereby npGH increases DNA damage and promotes EMT to enable a microenvironment favoring BPH development. Prostate GHR signaling may be an attractive therapeutic target for BPH.

Authors

Masaki Ryuzaki, Svetlana Zonis, Neil A. Bhowmick, Sandrine Billet, Saravana Kumar Kailasam Mani, Stephen J. Freedland, Hyung L. Kim, Vera Chesnokova, Shlomo Melmed

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Figure 1

Prostate npGH and γH2AX expression increases with age.

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Prostate npGH and γH2AX expression increases with age. (A–C) Representat...
(A–C) Representative IHC images of GH expression (brown, cytoplasmic) in normal human prostate tissue specimens derived from individual patients aged (A) 35, (B) 47, or (C) 70 years. Scale bars: 100 μm. GH is expressed in both epithelial cells and in stroma in the aged group. (D and E) Graphs depict percentage of prostate tissue samples positive for GH in (D) epithelial cells and (E) stroma. IHC scores of ≥55 for epithelial cells and ≥32 for stroma were considered positive. Each dot represents an individual patient sample with positive GH expression. Results were analyzed by χ2 test, as shown in Supplemental Figure 1, A and B. (F) Western blot of GH expression in individual prostate tissues derived from C57BL/6 WT male mice aged 4–6 months and 24 months. ImageJ quantifications of Western blots are depicted in Supplemental Figure 1D. (G) Prostate weight and (H) prostate weight/body weight ratio in WT or GHR–/– mice aged 4–6 months and 24 months. (I–N) Representative IHC images of γH2AX expression (brown, intranuclear) in normal human prostate tissue specimens derived from patients aged (I and J) 28, (K and L) 40, or (M and N) 72 years. Magnification is ×10 in I, K, and M, and ×20 in insets in J, L, and N. Scale bars: 100 μm. (O and P) Graphs depict percentage of prostate tissue samples positive for γH2AX in (O) epithelial cells and (P) stroma. IHC scores of ≥22 for epithelial cells and ≥11 for stroma were considered positive. Each dot represents an individual patient sample with positive γH2AX. Results were analyzed by χ2 test, as shown in Supplemental Figure 1, E and F. *P < 0.05; **P < 0.01; ***P < 0.001.