Retinoic Acid Receptor-Related Orphan Receptors: Critical Roles in Tumorigenesis

Abstract

Retinoic acid receptor-related orphan receptors (RORs) include RORα (NR1F1), RORβ (NR1F2), and RORγ (NR1F3). These receptors are reported to activate transcription through ligand-dependent interactions with co-regulators and are involved in the development of secondary lymphoid tissues, autoimmune diseases, inflammatory diseases, the circadian rhythm, and metabolism homeostasis. Researches on RORs contributing to cancer-related processes have been growing, and they provide evidence that RORs are likely to be considered as potential therapeutic targets in many cancers. RORα has been identified as a potential therapeutic target for breast cancer and has been investigated in melanoma, colorectal colon cancer, and gastric cancer. RORβ is mainly expressed in the central nervous system, but it has also been studied in pharyngeal cancer, uterine leiomyosarcoma, and colorectal cancer, in addition to neuroblastoma, and recent studies suggest that RORγ is involved in various cancers, including lymphoma, melanoma, and lung cancer. Some studies found RORγ to be upregulated in cancer tissues compared with normal tissues, while others indicated the opposite results. With respect to the mechanisms of RORs in cancer, previous studies on the regulatory mechanisms of RORs in cancer were mostly focused on immune cells and cytokines, but lately there have been investigations concentrating on RORs themselves. Thus, this review summarizes reports on the regulation of RORs in cancer and highlights potential therapeutic targets in cancer.

Keywords: RORα; RORβ; RORγ; cancer; retinoic acid receptor-related orphan receptors.

Figure 1

Expression and function of receptor-related orphan receptors (RORs) in tumor microenvironment. The expression of RORα and RORβ from tumor cell and the modulated expression of RORγ in group 3 innate lymphoid cells (ILC3), Th17, regulatory T cell (Treg), myeloid cell, and tumor cell from tumor microenvironment are presented as reviewed in the text. The downregulation of RORα and RORβ induce antitumor effect in hepatoma, breast cancer (BC), melanoma, and colon cancer. The upregulation of RORγ in ILC3 leads to protumor effect by chemokines in BC. The downregulation of RORγ in Th17 indicates antitumor effect by IL-17 in colon cancer. The upregulation of RORγ in Treg shows protumor effect in colon cancer. The expression of RORγ in myeloid cell has protumor effects via Socs3, Bcl3, and C/EBPb. The expression of RORγ in tumor cell is either increased or decreased depending on the cancer type. Increased expression of RORγ in lung cancer, prostate cancer, and gastric cancer results in protumor effect, while decreased expression of RORγ in BC and melanoma could induce antitumor effect via TGFβ/epithelial–mesenchymal transition (EMT) or vitamin D3 derivatives. The question mark refers to unknown mechanisms. The up or down black arrow refers to upregulation or downregulation. Antitumor: inhibits tumor progression; protumor: promotes tumor progression.