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Decreased Expression of Wilms’ Tumor Gene WT-1 and Elevated Expression of Insulin Growth Factor-II (IGF-II) and Type 1 IGF Receptor Genes in Prostatic Stromal Cells from Patients with Benign Prostatic Hyperplasia¹

Children’s Hospital of Philadelphia, University of Pennsylvania, (G.D., R.R., P.C.), Philadelphia, Pennsylvania 19104; Departments of Urology (D.M.P.) and Medicine (A.R.H., T.V.), Stanford University Medical Center, Palo Alto, California 94305; and Department of Pediatrics, Oregon Health Sciences University (C.T.R., R.G.R.), Portland, Oregon 97201

Address all correspondence and requests for reprints to: Pinchas Cohen, Pediatric Endocrinology, Children’s Hospital of Philadelphia, University of Pennsylvania, Room 410-D Abramson Research Center, 3400 Civic Center Boulevard, Philadelphia, Pennsylvania 19104. E-mail: cohenp{at}email.chop.edu

Benign prostatic hyperplasia (BPH) is a common proliferative disorder of unknown etiology. We have previously documented that the insulin-like growth factor (IGF) axis is critical for prostate cell growth and is abnormal in BPH. The type 1 IGF receptor (IGF-1R) is constitutively expressed by most body tissues and plays a significant role in regulating cell proliferation, consistent with the role of its ligands (IGF-I and IGF-II) as important mitogenic factors. The Wilms’ tumor gene product (WT-1) is a tumor suppressor that has been shown to be altered in rare kidney tumors and is known to regulate IGF-II and IGF-1R. We investigated the possibility that the expression of prostatic WT-1, IGF-1R, and IGF-II genes is altered in patients with BPH. We utilized primary cultures of prostatic stromal cells grown from normal (n = 9) and hyperplastic (n = 9) surgical specimens and analyzed WT-1, IGF-1R, and IGF-II messenger RNA levels. In all of the BPH cell strains, WT-1 expression (measured by RT-PCR and RNase protection assays) was strikingly lower than that found in normal strains (0–20% of normal, mean 14% of normal, P < 0.01). The expression of both the IGF-1R (300% of normal, P < 0.05) and IGF-II (1000% of normal, P < 0.01) messenger RNAs was higher in BPH strains as compared with normal strains. No changes were seen in stromal cell strains derived from prostatic adenocarcinoma. Thus, in cultured human prostatic stromal cell strains from patients with BPH, decreased WT-1 gene expression is associated with increases in the expression of the IGF-1R and IGF-II genes that are known transcriptional targets of WT-1. These findings indicate that reduced expression of the WT-1 tumor suppressor gene and elevated IGF-1R and IGF-II gene expression may be involved in the pathophysiology of prostatic hyperplasia, implying a new role for the Wilms’ tumor gene in nonmalignant states.

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