Studies of the effect of transforming growth factor-beta on PTHrP expression,mRNA stability, and secretion in epithelial cancers

Parathyroid hormone related protein (PTHrP) is similar to parathyroid hormone (PTH) and amino-termini of both proteins bind PTH1 receptors (PTH1R) in bone and kidney to increase blood calcium. Epithelial tumors such as squamous cell carcinoma may over express and secrete PTHrP into the systemic circulation to cause humoral hypercalcemia of malignancy (HHM). Increased levels of PTHrP have also been implicated in prostate cancer bone metastases.; The occurrence of HHM in patients with head and neck squamous cell carcinomas (HNSCC) was examined in 55 HNSCC patients. No patients had increased plasma PTHrP, serum ionized calcium, or altered urine calcium/creatinine. This data indicated that HHM was rare in patients with HNSCC.; TGFβ1 has been shown to increase PTHrP mRNA transcription and mRNA stability. The role of the 3′-untranslated region (3 ′UTR) of PTHrP (1–141) mRNA stability was examined and demonstrated that coding region sequences were likely important in TGFβ1-induced PTHrP mRNA stability. In addition, TGFβ1 treatment of cells resulted in decreased mRNA-protein binding to the terminal coding region.; PTHrP has a complex gene structure with 3 promoters, P1, P2, and P3, which is alternatively spliced into 3 isoforms encoding 139, 173, and 141 amino acid proteins. PTHrP mRNA (1–139 and 1–141) half-life in canine squamous carcinoma cells (SCC2/88) and human squamous carcinoma cells (HARA) was short (45 min–2 hrs) and that of PTHrP (1–173, not present in dogs) was 2–5-fold that of the other isoforms. TGFβ1 increased the mRNA half-life of only PTHrP (1–141). TGFβ1 treatment. Increased secretion of PTHrP into SCC2/88 conditioned medium but not the HARA cells. TGFβ1 treatment increased the P1 promoter use in both HARA and SCC2/88.; PTHrP and TGFβ1 as well as endothelin-1 (ET-1) have been implicated in the induction of new woven bone formation to form osteoblastic metastases in prostate cancer. TGFβ1 did not increase ET-1 mRNA expression in any prostate cells. TGFβ1 increased PTHrP mRNA expression and protein secretion in prostate epithelial cells (PEC) and in prostate carcinoma cells (PCC), but decreased PTHrP mRNA in prostate stromal cells (PSC).