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

Yan C, Lei Y, Lin TJ, Hoskin DW, Ma A, Wang J
Oncotarget. 2017 8 (26): 43153-43168

PMID: 28562353 · PMCID: PMC5522135 · DOI:10.18632/oncotarget.17820

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.

MeSH Terms (19)

Animals Cell Line, Tumor Cell Proliferation Female Interleukin-17 Isoenzymes Male Mammary Neoplasms, Experimental MAP Kinase Kinase 4 Melanoma Melanoma, Experimental Mice Mice, Inbred BALB C Mice, Inbred C57BL Receptors, Interleukin-17 Signal Transduction Transcription Factors Transfection Tumor Necrosis Factor alpha-Induced Protein 3

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