ALV-J and REV synergistically activate a new oncogene of KIAA1199 via NF-κB and EGFR signaling regulated by miR-147

Abstract

22The tumorigenesis is the result of the accumulation of multiple oncogenes and tumor 23 suppressor genes changes. Co-infection of avian leucosis virus subgroup J (ALV-J) 24 and reticuloendotheliosis virus ( REV) , as two oncogenic retroviruses, showed 25 synergistic pathogenic effects characterized by enhanced tumor initiation and 26 progression. The molecular mechanism underlying synergistic effects of ALV-J and 27 REV on the neoplasia remains unclear. Here, we found co-infection of ALV-J and 28 REV enhanced the ability of virus infection, increased viral life cycle, maintained cell 29 survival and enhanced tumor formation. We combined the high-throughput proteomic 30 readout with a large-scale miRNA screening to identify which molecules are involved 31 in the synergism. Our results revealed co-infection of ALV-J and REV activated a 32 latent oncogene of KIAA1199 and inhibited the expression of tumor suppressor miR-33 147. Further, enhanced KIAA1199, down-regulated miR-147, activated NF-κB and 34 EGFR were demonstrated in co-infected tissues and tumor. Mechanistically, we 35 showed ALV-J and REV synergistically enhanced KIAA1199 by activation of NF-κB 36 and EGFR signalling pathway, and the suppression of tumor suppressor miR-147 37 was contributed to maintain the NF-κB/KIAA1199/EGFR pathway crosstalk by 38 targeting the 3'UTR region sequences of NF-κB p50 and KIAA1199. Our results 39 contributed to the understanding of the molecular mechanisms of viral synergistic 40 tumorgenesis, which provided the evidence that suggested the synergistic actions of 41 two retroviruses could result in activation of latent pro-oncogenes. 42 Author summary 3 43The tumorigenesis is the result of the accumulation of multiple oncogenes and tumor 44 suppressor genes changes. Co-infection with ALV-J and REV showed synergistic 45 pathogenic effects characterized by enhanced tumor progression, however, the 46 molecular mechanism on the neoplasia remains unclear. Our results revealed co-47 infection of ALV-J and REV promotes tumorigenesis by both induction of a latent 48 oncogene of KIAA1199 and suppression of the expression of tumor suppressor miR-49 147. Mechanistic studies revealed that ALV-J and REV synergistically enhance 50 KIAA1199 by activation of NF-κB and EGFR signalling pathway, and the suppression 51 of tumor suppressor miR-147 was contributed to maintain the NF-52 κB/KIAA1199/EGFR pathway crosstalk by targeting the 3'UTR region sequences of 53 NF-κB p50 and KIAA1199. These results provided the evidence that suggested the 54 synergistic actions of two retroviruses could result in activation of latent pro-55 oncogenes, indicating the potential preventive target and predictive factor for ALV-J 56 and REV induced tumorigenesis. 57 Introduction 58 Viral synergism occurs commonly in the nature when co-infection of two or more 59 unrelated viruses invades the same host. As two oncogenic retroviruses, avian 60 leukosis virus subgroup J (ALV-J) and reticuloendotheliosis virus (REV) are the 61 optimal model to study the synergisti...