Oncogenic potential of truncated RXRα during colitis-associated colorectal tumorigenesis by promoting IL-6-STAT3 signaling

• Published in: Nature communications 2019-04, Vol.10 (1), p.1463-15, Article 1463
• Main Authors: Ye, Xiaohong, Wu, Hua, Sheng, Luoyan, Liu, Yi-xin, Ye, Fang, Wang, Mo, Zhou, Hu, Su, Ying, Zhang, Xiao-kun
• Format: Article
• Language: English
• Subjects: 13/51; 42/109; 42/41; 49/90; 631/67; 631/80; 631/80/304; 64/110; 64/60; 82/1; 96/21; 96/95; Animals; Anti-inflammatory agents; Cancer; Carcinogenesis - genetics; Carcinogenesis - immunology; Cell activation; Colitis; Colitis - genetics; Colitis - immunology; Colitis, Ulcerative - immunology; Colon; Colon - drug effects; Colon - immunology; Colon - metabolism; Colon cancer; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - immunology; Culture Media, Conditioned; Cytoplasm; Disease Models, Animal; HCT116 Cells; Humanities and Social Sciences; Humans; Inflammation; Inflammatory bowel disease; Interleukin 6; Interleukin-6 - immunology; Macrophages; Macrophages - immunology; Mice; multidisciplinary; Myeloid cells; NF-kappa B - immunology; NF-κB protein; Nonsteroidal anti-inflammatory drugs; Retinoid X Receptor alpha - genetics; Retinoid X Receptor alpha - immunology; Science; Science (multidisciplinary); Signal Transduction; Signaling; Stat3 protein; STAT3 Transcription Factor - immunology; Sulindac; Sulindac - analogs & derivatives; Sulindac - pharmacology; TNF Receptor-Associated Factor 6 - immunology; TRAF6 protein; Tumor cells; Tumorigenesis; Tumors; Ubiquitination
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-09375-8

Retinoid X receptor-alpha (RXRα) is a potent regulator of inflammatory responses; however, its therapeutic potential for inflammatory cancer remains to be explored. We previously discovered that RXRα is abnormally cleaved in tumor cells and tissues, producing a truncated RXRα (tRXRα). Here, we show that transgenic expression of tRXRα in mice accelerates the development of colitis-associated colon cancer (CAC). The tumorigenic effect of tRXRα is primarily dependent on its expression in myeloid cells, which results in interleukin-6 (IL-6) induction and STAT3 activation. Mechanistic studies reveal an extensive interaction between tRXRα and TRAF6 in the cytoplasm of macrophages, leading to TRAF6 ubiquitination and subsequent activation of the NF-κB inflammatory pathway. K-80003, a tRXRα modulator derived from nonsteroidal anti-inflammatory drug (NSAID) sulindac, suppresses the growth of tRXRα-mediated colorectal tumor by inhibiting the NF-κB-IL-6-STAT3 signaling cascade. These results provide new insight into tRXRα action and identify a promising tRXRα ligand for treating CAC. The truncated form of retinoid X receptor-alpha is found in cancer. Here, the authors show that this mutant receptor promotes colorectal tumorigenesis by activation of NF-κB in myeloid cells, leading to subsequent IL-6-induced STAT3 activation in intestinal epithelial cells, which can be suppressed by ligand K-80003.