Exploring the Link Between PACAP Signalling and Hyaluronic Acid Production in Melanoma Progression

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a small neuropeptide detected first in the hypothalamo-hypophyseal system; recently, it has also been identified in peripheral organs and in tumours. It is well demonstrated that PACAP exerts cell- and tissue-protecting effects in various stressful conditions and helps to maintain tissue homeostasis. In melanoma, the anti-invasive effect of PACAP has been demonstrated; however, there is also existing sporadic data which proves PACAP plays a role in melanoma progression. The major goal of our study was to investigate the signalling targets of PACAP in A2058 and WM35 melanoma cell lines in vitro. Various molecular players of melanocyte differentiation and function responded to PACAP application. SOX9 expression increased while SOX10 expression decreased and CREB signalling did not change. The expression level of TYRP1 decreased, while DCT elevated, and MITF expression showed changes at the mRNA level and in its subcellular localisation. In contrast, the amount of hyaluronan (HA) and expressions of its synthases, as well as RHAMM, increased, indicating the role of PACAP in secretion of an HA-rich matrix. In parallel with these results, we detected elevated hyaluronidase2 (Hyal2) expression in the presence of PACAP. On the other hand, alfaV and beta3 integrin expressions did not alter significantly. Our results demonstrate that exogenous PACAP modulates the expression of multiple target molecules in melanoma cells. Some of the significantly responding molecules take part in hyaluronan homeostasis, suggesting an effect of PACAP on tumour matrix composition, through which it can modulate invasiveness of melanoma cells.