RORα and RORγ expression inversely correlates with human melanoma progression

The retinoic acid-related orphan receptors (RORs) regulate several physiological and pathological processes, including immune functions, development and cancer. To study the potential role of RORs in melanoma progression, we analysed ROR alpha and ROR gamma expression in nevi and primary melanomas and non-lesional skin and metastases in relation to melanoma clinico-pathomorphological features. The expression of ROR alpha and ROR gamma was lower in melanomas than in nevi and decreased during melanoma progression, with lowest levels found in primary melanomas at stages III and IV and in melanoma metastases. Their expression correlated with pathomorphological pTNM parameters being low in aggressive tumors and being high in tumors showing histological markers of good prognosis. Higher nuclear levels of ROR alpha and ROR gamma and of cytoplasmic ROR gamma correlated with significantly longer overall and disease free survival time. Highly pigmented melanomas showed significantly lower level of nuclear RORs. This study shows that human melanoma development and aggressiveness is associated with decreased expression of ROR alpha and ROR gamma, suggesting that RORs could be important in melanoma progression and host responses against the tumor. Furthermore, it suggests that ROR alpha and ROR gamma might constitute a novel druggable target in anti-melanoma management using tumor suppressor gene therapy restoring their normal functions.