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.
Original language | English |
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Pages (from-to) | 548-558 |
Number of pages | 11 |
Journal | International Journal of Cancer |
Volume | 145 |
Issue number | 2 |
DOIs | |
Publication status | Published - Jul 15 2019 |
Bibliographical note
Funding Information:We would like to thank Mrs. Hana James, Fang Liu and Rachel Clarke for technical assistance, as well as Philippe Fullsack for assistance in conducting statistical analyses. CY was supported by a graduate student scholarship from the IWK Health Centre and received a trainee award from the Beatrice Hunter Cancer Research Institute, with funds provided by the Cancer Research Training Program, as part of The Terry Fox Foundation Strategic Health Research Training Program in Cancer Research in CIHR.
Funding Information:
We would like to thank Mrs. Hana James, Fang Liu and Rachel Clarke for technical assistance, as well as Philippe Fullsack for assistance in conducting statistical analyses. CY was supported by a graduate student scholarship
Publisher Copyright:
© 2019 UICC
ASJC Scopus Subject Areas
- Oncology
- Cancer Research