IL‐17R deletion predicts high‐grade colorectal cancer and poor clinical outcomes.

The IL‐17 receptor (IL‐17R) has a perplexing role in cancer, which may be explained by its yin‐yang signaling pathways. Recently, the critical role of IL‐17R in maintaining basal levels of A20—a key negative regulator of NF‐κB and JNK‐c‐Jun pathways has been demonstrated in cancer cell lines. Cross‐cancer analyses of somatic copy number alterations in IL‐17RA, IL‐17RC and A20 genes reveal that IL‐17RA‐deletion is common in colorectal cancer (CRC) patients, representing 24, 26, 37 and 49% of stage I, II, III and IV of patients, respectively, and mutually exclusive with patients displaying microsatellite instability. Importantly, patients with IL‐17R‐deletion or concurrent deletions of A20 show significantly reduced overall survival. Analysis of multiple published microarray studies confirms that IL‐17RA expression is significantly reduced in CRC samples compared to normal counterparts, and its level is closely associated with A20 expression. Analyses of RNAseq data indicate that tumors with IL‐17R‐deletion express strong molecular markers of tumor invasion, growth and metastasis. Notably, approximately 20 genes responsible for protein synthesis and mitochondrial metabolism are inversely correlated with both IL‐17RA and A20. Immunohistochemistry staining in human colorectal tissue arrays further reveals that high‐grade tumors have significantly reduced IL‐17RA staining compared to low‐grade tumors. Thus, collective evidence strongly supports a previously unrecognized CRC‐promoting mechanism triggered by IL‐17RA‐deletion and highlights its utility as a prognostic marker in CRC. What's new? Interleukin‐17 signaling plays an important, complex role in inflammation and colorectal cancer. Here, the authors show that high grade tumors have far less IL‐17 receptor than low grade tumors. They also found that IL‐17R levels correlate closely with the ubiquitin‐editing enzyme A20, which helps keep a lid on inflammation by regulating NF‐kB. Patients with reduced IL‐17R had worse overall survival, and tumors carrying deletions in IL‐17R had significant changes in the NF‐kB and MAPK signalling pathways. Together, these data suggest that IL‐17R deletions could be useful as a prognostic marker for CRC patients. [ABSTRACT FROM AUTHOR]