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 6

GH suppresses DNA damage repair pathways in HPrECs.

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GH suppresses DNA damage repair pathways in HPrECs. RNA-seq conducted on...
RNA-seq conducted on RNA extracted from HPrEC line 1 or HPrEC line 2 with or without treatment of 100 ng/mL GH for 24 hours. Results from 3 independent experiments shown. (A) Bar plot showing DNA repair related pathways identified by over-representation analysis. The x axis (enrichment ratio) represents the ratio of differentially expressed genes (DEGs) within a specific pathway to the total number of genes annotated to that pathway. The number of DEGs within each pathway is given next to its respective bar. P value is indicated by color of the bar. (B and C) Heatmaps of 5 representative genes associated with the DNA damage repair pathway showing significant downregulation in response to GH treatment in (B) HPrEC line 1 or (C) HPrEC line 2. (D) Real-time PCR of mRNA expression of genes identified as significantly suppressed by RNA-seq in HPrEC line 2 treated with 100 ng/mL GH for 24 hours. Normalized PCR results are expressed as fraction of control taken as 1. The experiment was performed in triplicate. Differences were assessed with 2-tailed Student’s t test. *P < 0.05, **P < 0.01 versus control. (E) Western blot of DNA repair protein expression in HPrEC line 2 treated with indicated doses of GH for 24 hours. Representative blots from at least 3 independent experiments are shown. ImageJ quantification is depicted in Supplemental Figure 6.