RORα and RORγ expression inversely correlates with human melanoma progression

// Anna A. Brożyna 1, 2 , Wojciech Jóźwicki 1, 2 , Cezary Skobowiat 3 , Anton Jetten 4 , Andrzej T. Slominski 5,6, 7 1 Department of Tumor Pathology and Pathomorphology, Oncology Centre - Prof. Franciszek Łukaszczyk Memorial Hospital, Bydgoszcz, Poland 2 Department of Tumor Pathology and Pathomorphology, Faculty of Health Sciences, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland 3 Department of Pharmacodynamics and Molecular Pharmacology, Faculty of Pharmacy, Nicolaus Copernicus University Collegium Medicum in Bydgoszcz, Bydgoszcz, Poland 4 Cell Biology Section, Immunity, Inflammation and Disease Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA 5 Department of Dermatology, Cancer Chemoprevention Program, University of Alabama at Birmingham, AL, USA 6 Comprehensive Cancer Center, Cancer Chemoprevention Program, University of Alabama at Birmingham, AL, USA 7 Pathology and Laboratory Medicine Service, VA Medical Center, Birmingham, AL, USA Correspondence to: Anna A. Brożyna, email: anna.brozyna@cm.umk.pl Andrzej T. Slominski, email: aslominski@uabmc.edu Keywords: melanoma, RORα, RORγ, melanocytic nevi, vitamin D Received: February 19, 2016 Accepted: July 18, 2016 Published: August 11, 2016 ABSTRACT 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 RORα and RORγ expression in nevi and primary melanomas and non-lesional skin and metastases in relation to melanoma clinico-pathomorphological features. The expression of RORα and RORγ 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 RORα and RORγ and of cytoplasmic RORγ 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 RORα and RORγ, suggesting that RORs could be important in melanoma progression and host responses against the tumor. Furthermore, it suggests that RORα and RORγ might constitute a novel druggable target in anti-melanoma management using tumor suppressor gene therapy restoring their normal functions.