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

Abstract

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.

Decreased interleukin‐17RA expression is associated with good prognosis in patients with colorectal cancer and inhibits tumor growth and vascularity in mice

“…In our unpublished data indicates the IL‐17RA overexpression promotes cancer stem‐like properties of CRC cells by Stat3 activation 24 . However, a study revealed that the deletion of IL‐17RA in CRC is linked to the degradation of A20, which is a negative regulator of the NF‐κB, WNT, and JNK‐c‐Jun signaling pathways, and associated with poor clinical outcome 18 . Another study revealed that the low or loss of IL‐17RA is significantly associated with advanced stage tumors 17 .…”

“…24 However, a study revealed that the deletion of IL-17RA in CRC is linked to the degradation of A20, which is a negative regulator of the NF-κB, WNT, and JNK-c-Jun signaling pathways, and associated with poor clinical outcome. 18 Another study revealed that the low or loss of IL-17RA is significantly associated with advanced stage tumors. 17 In the present study, no abnormality was found in endogenous IL-17RA expression in CRC tissues and adjacent normal tissues.…”

Pro-inflammatory polarization and colorectal cancer modulate alternative and intronic polyadenylation in primary human macrophages

“…Interleukin 17A and its receptor IL17RA play a pathogenic role in many inflammatory and autoimmune diseases and IL17RA contributes to the inflammatory response by inducing recruitment of innate immune cells 54 . In addition, IL17RA deletion predicts high-grade colorectal cancer and poor clinical outcomes 55 . TP53RK (TP53 Regulating Kinase) is another example of a gene that displays a decrease in the expression of the longest 3’UTR mRNA isoform and an upregulation of the shortest 3’UTR mRNA isoform in M1 vs M0 (Figure 3D).…”

Interleukin-17 signaling influences CD8+T cell immunity and tumor progression according to the IL-17 receptor subunit expression pattern in cancer cells

“…Differences in tumor IL-17RA expression levels correlated with differences in overall survival time in SKCM patients with high tumor IL-17RC expression but not in LAML patients with low tumor IL-17RC expression while the expression levels of IL-17RC itself or IL-17RD were not associated with differences in survival in any of the cohorts. Recently, deletion of IL17RA or IL-17RC in the colon was associated with advances stages and a worse prognosis in colorectal cancer prognosis (88). In addition, other studies evaluating the role of the IL-17 pathway in cancer patients highlighted that IL-17A levels were more frequently associated with a worse prognosis although an association with improved survival was also reported not only for tumors of different histological origin but also for the same tumor type (11).…”