Parathyroid hormone related peptide (PTHrP) favors a more aggressive phenotype in colorectal cancer derived cells through the positive modulation of its own expression.

MARTIN MARIA JULIA; CARRIERE PEDRO; NOVOA DIAZ MARÍA BELEN; CALVO NATALIA; GENTILI CLAUDIA

Buenos Aires

Congreso; 2° CONGRESO CONJUNTO DE OSTEOLOGÍA XXXV REUNIÓN ANUAL AAOMM XIII CONGRESO ARGENTINO DE OSTEOPOROSIS; 2018

Asociación Argentina de Osteología y Metabolismo Mineral

Parathyroid hormone-related protein (PTHrP), originally identified as the factor responsible for malignant hypercalcemia, was later found to be widely expressed in many tissues. Today it is recognized for its endocrine, paracrine, autocrine and intracrine modes of action. PTHrP is expressed in most patients with colorectal cancer (CRC). Several studies showed that PTHrP levels are higher in less differentiated CRC than in those with a higher degree of differentiation. In cells derived from CRC we previously found that the calciotropic hormones PTH and calcitriol, which exert anti-proliferative effects on these cells, down-regulate PTHrP mRNA levels and that exogenous PTHrP induces cell cycle progression, cell migration and exerts proliferative and protective effects. The aim of this study was to evaluate if the hormone modulates its own expression in intestinal tumor cells and if endogenous over-expression of PTHrP exerts the same effects observed for exogenous PTHrP. qPCR analysis revealed that PTHrP mRNA levels were very low in Caco-2 and HCT116 cells. However, PTHrP treatment for 20 hours significantly increased (4,5 fold) PTHrP transcription in Caco-2 cells, which are functionally similar to normal enterocytes. No changes were observed in HCT116 cells which are less differentiated and show a more aggressive phenotype. By cell proliferation assays we observed that the PTHrP overexpression favors the proliferation of intestinal tumor cells. Western blot analysis revealed that, like exogenous PTHrP, the peptide endogenously over-expressed by intestinal tumor cells induces the activation of MAPKs and Akt and modulates the protein expression of certain cell cycle regulators. These findings suggest that a mechanism activated by exogenous PTHrP leading to a more aggressive phenotype of cells derived from CRC may be the modulation of its own expression. This work contributes to elucidate the action of this hormone in the genesis and progression of CRC.