Research Papers:

IL-17RC is critically required to maintain baseline A20 production to repress JNK isoform-dependent tumor-specific proliferation

Chi Yan, Yang Lei, Tong-Jun Lin, David W. Hoskin, Averil Ma and Jun Wang _

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Oncotarget. 2017; 8:43153-43168. https://doi.org/10.18632/oncotarget.17820

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Chi Yan1,2, Yang Lei1,2, Tong-Jun Lin2,3,5, David W. Hoskin2,4, Averil Ma6 and Jun Wang1,2,3,5

1Canadian Center for Vaccinology, Halifax, Nova Scotia, Canada

2Department of Microbiology and Immunology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada

3Department of Pediatrics, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada

4Department of Pathology, Dalhousie University, Halifax, Nova Scotia, Canada

5IWK Health Centre, Halifax, Nova Scotia, Canada

6Department of Medicine, University of California, San Francisco, California, USA

Correspondence to:

Jun Wang, email: [email protected]

Keywords: IL-17 receptor C, A20, JNK1, JNK2, B16 melanoma

Received: February 04, 2017     Accepted: April 17, 2017     Published: May 11, 2017


The IL-17/IL-17R axis has controversial roles in cancer, which may be explained by tumor-specific results. Here, we describe a novel molecular mechanism underlying IL-17RC-controlled tumor-specific proliferation. Triggered by IL-17RC knockdown (KD), B16 melanoma and 4T1 carcinoma cells inversely altered homeostatic tumor proliferation and tumor growth in vitro and in vivo. In contrast to the existing dogma that IL-17RC-dependent signaling activates the JNK pathway, IL-17RC KD in both tumor cell lines caused aberrant expression and activation of different JNK isoforms along with markedly diminished levels of the ubiquitin-editing enzyme A20. We demonstrated that differential up-regulation of JNK1 and JNK2 in the two tumor cell lines was responsible for the reciprocal regulation of c-Jun activity and tumor-specific proliferation. Furthermore, we showed that A20 reconstitution of IL-17RCKD clones with expression of full-length A20, but not a truncation-mutant, reversed aberrant JNK1/JNK2 activities and tumor-specific proliferation. Collectively, our study reveals a critical role of IL-17RC in maintaining baseline A20 production and a novel role of the IL-17RC-A20 axis in controlling JNK isoform-dependent tumor-specific homeostatic proliferation.

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