High serum calcium (Ca) due to aberrant secretion of tumor parathyroid hormone-like hormone (PTHLH) is a well-known paraneoplastic sign and is associated with poor prognosis in patients with renal cell carcinoma (RCC).
Our goals were to analyze the alternative splicing of PTHrP mRNA in human RCC and from these results to identify VHL/hypoxia-induced factor (HIF) system-regulated mRNA-binding proteins involved in PTHrP mRNA stability.
Using specific inhibitors of phosphoinositide 3-kinase (PI3K) and depletion of Akt kinase by RNA interference, we established that PTHrP is one of the main factor involved in the constitutive activation of this pathway in human RCC, independently of von Hippel-Lindau (VHL) tumor suppressor gene expression.
The antitumor activity of PTHrP neutralizing antibody and of PTH1R antagonist were evaluated in vitro and in vivo in a panel of human RCC lines expressing or not pVHL.
Hypercalcemia in patients with renal cell carcinoma frequently mimics primary hyperparathyroidism and has been attributed to tumor secretion of parathyroid hormone related protein.
To identify these secretory forms, medium was harvested from three cell types: human renal carcinoma (SKRC-1) cells, human keratinocytes, and rat insulinoma cells stably transfected with the cDNA for PTHrP(1-141) (RIN-141 cells).