Sonic Hedgehog signaling pathway is expressed in normal human adrenal cortices and up-regulated in adrenocortical carcinomas

Abstract

The Sonic Hedgehog (Shh) signaling pathway is involved in mouse adrenal growth and differentiation. However, it remains unclear whether this pathway plays a similar role in human especially because we previously showed that this organ displays a significant capacity for tissue regeneration from differentiated cells. The expression of the components of the pathway was examined in 38 normal adult adrenal glands and 23 adrenocortical carcinomas (ACCs). We found that Shh is widely expressed in steroidogenic cells. Shh-positive cells also expressed the Shh receptor Patched-1 as well as the receptor-like signal transducer Smoothened. Moreover, expression of the transcription factors Gli1, Gli2 and Gli3 was detected in the nucleus of the steroidogenic cells. Our data identified Shh pathway as a new autocrine/paracrine loop in human steroidogenic cells. However, we cannot exclude that a subpopulation of cells may correspond to stem/progenitor cells since non-steroidogenic cells located in the capsule express components of the Shh pathway. ACCs exhibited an increased expression of all components of Shh pathway with the exception of Gli2 indicating a possible involvement in the tumorigenic process. In addition, the Smoothened inhibitor NVP-LDE225 potently inhibited tumor growth and reduced cortisol and aldosterone secretion by H295R cells. We also showed that LDE225 acts by targeting mitochondria leading to a decrease in transmembrane potential and an increase in ROS production. Collectively, our findings show that Shh pathway is expressed in normal human steroidogenic cells and is activated in carcinomas. Shh may be a promising target for the treatment of this aggressive cancer.