|Ph.D Student||Baidosee Maslama|
|Subject||The Involvement of Human Growth Hormone and its|
Receptors in Prostate Cancer
|Department||Department of Medicine||Supervisor||Assistant Professor Ronnie Barkey|
|Full Thesis text|
Various hormones and growth factors (GFs) have been implicated in progression of prostate cancer (PCa), but their role remains poorly understood. In this study, we investigated the role of GH and its receptor (GHR) in PCa. We first demonstrated mRNA expression of full length GHR and of its truncated isoform (GHRtr) in benign prostate hyperplasia (BPH) and PCa patient tissues, as well as in androgen-sensitive LNCaP and androgen-independent (AI), PC3 and DU145 human PCa cell lines. We report for the first time the expression of GHRtr in LNCaP and DU145 cells and that GHR and GHRtr mRNA levels were higher in the PCa tissues than in BPH. We demonstrate for the first time, that GHR binding capacity in LNCaP cells is subject to hormonal up-regulation (by androgen, estrogen (E2), cortisol, thyroid hormone (T3) (≤ 24 h), insulin-like growth factor (IGF)-I and IGF-II) or down-regulation (by T3, >24 h) in dose- and time-dependent manners. In addition, we observed a differential regulation of the gene expression of the two GHR isoforms, of the IGF system genes, especially IGF-I receptor (IGF-IR), and of estrogen receptor (ER) gene, by GH, by gonadal steroids and by T3: in LNCaP cells hGH increased GHR, GHRtr, IGF-I, IGF-IR, IGF-IIR and ERβ mRNA levels; in PC3 cells GH increased GHRtr, IGF-II, IGF-IIR and ERβ while decreasing IGF-IR mRNAs; in DU145 cells GH inhibited GHR and GHRtr expression. Mibolerone, a potent androgen analog, stimulated GHR and (more prominently) GHRtr, ERβ and IGF-I, IGF-IR while inhibiting IGF-IIR in LNCaP cells; T3 (6 h) up-regulated GHR, GHRtr, IGF-I, IGF-IR, IGF-IIR and ERβ gene expression; the rapid T3 effect on GHR was opposed by added hGH, however, exposure to T3 for longer times (24 h) decreased GHR gene expression. We also demonstrated that expression of ERα mRNA was detected only in PC3 and DU145 cells, whereas ERβ mRNA was observed in all three cell lines; E2, induced GHRtr, IGF-I, IGF-IR, IGF-IIR and ERβ mRNA. Finally, we found that IGF-I and IGF-II mRNA were detected in LNCaP and in PC3 and DU145 cells, respectively. All three cell lines expressed similar levels of IGF-IR and IGF-IIR. Importantly, we demonstrated for the first time, that in LNCaP cells, the combinations of hGH with E2 or with IGF-I might have synergistic/permissive proliferative effects, respectively.
Our findings indicate that GH and GHRs, most likely in concert with other hormones/GFs, potentially play an important role in PCa.