IL-17B/IL-17RB signaling regulates lysine 63-linked Beclin-1 ubiquitination to strengthen self-renewal and tumorigenesis in gastric cancer
作者单位：Department of Laboratory Medicine Affiliated Hospital of Jining Medical University Institute of Forensic Medicine and Laboratory Medicine Jining Medical University
会议名称：《中国生物化学与分子生物学会2019年全国学术会议暨学会成立四十周年》
会议日期：2019年
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
关 键 词：IL-17B IL-17RB autophagy K63-linked ubiquitination of Beclin-1 gastric cancer cancer stem cell
摘 要：Cancer stem cells(CSCs) display many malignant biological traits including tumorigenesis, metastasis, drug resistance and angiogenesis. Discovering new markers specific for CSCs and elucidating their regulatory mechanisms is a significant goal. Herein, we found that IL-17 B/IL-17 RB signaling promoted self-renewal and tumorigenesis of gastric cancer(GC) cells by activating autophagy. We identified this pathway by first determining that IL-17 RB expression is significantly upregulated in spheroid cells, which was closely associated with the degree of differentiation of patient-derived GC tissues. Exogenous recombinant IL-17 B(rIL-17 B) promoted the self-renewal capacity of GC cells in vitro and enhanced tumor growth and metastasis in vivo. Moreover, we found that rIL-17 B induced autophagosome formation and cleavage-mediated transformation of LC3 in GC and 293 T cells. Interestingly, inhibition of autophagy by ATG7 knockdown reversed rIL-17 B induced self-renewal of GC cells. Further study revealed that rIL-17 B promoted K63-linked ubiquitination of beclin-1 by mediating the binding of TRAF6 to beclin-1. Interfering with IL-17 RB expression abolished all the effects of rIL-17 B on ubiquitination of beclin-1 and autophagic activation of GC cells. Lastly, we discovered that IL-17 B expression in the serum of patients was positively correlated with IL-17 RB expression in GC tissues. In addition, rIL-17 B increased IL-17 RB expression in GC cells. Direct overexpression of IL-17 RB in 293 T cells mimics stimulated rIL-17 B, which promoted K63-linked ubiquitination of beclin-1 and binding of TRAF6 to beclin-1. Together, these results revealed the novel action of IL-17 B/IL-17 RB signaling on CSCs and might provide new therapeutic targets against gastric cancer.