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The Ap-2α/Elk-1 axis regulates Sirpα-dependent tumor phagocytosis by tumor-associated macrophages in colorectal cancer

查看全文 作　　者：Xiaojiao [1]Wang;Xi [1]Luo;Chuan [2]Chen;Ye [3]Tang;Lian [1]Li;Banghui [1]Mo;Houjie [1]Liang;Songtao [1]Yu 高影响力作者 机构地区：[1]Department of Oncology,Southwest Hospital,Army Medical University,30 Gaotanyan Street,Chongqing 400038,People’s Republic of China;[2]Cancer Center,Daping Hospital and Research Institute of Surgery,Army Medical University,Chongqing 402560,People’s Republic of China;[3]Department of Oncology,Tong Liang District Hospital,Chongqing 402560,People’s Republic of China高影响力机构 出　　处：《Signal Transduction and Targeted Therapy》索引2020年第5卷第1期,共12页高影响力期刊 基　　金：supported in part by award numbers 81972775(S.Y.),81602628(X.L.)from the National Natural Science Foundation of China;SWH2017YQPY-01(S.Y.)and SWH2016ZDCX1002(H.L.)from Southwest Hospital Research and 2018ZDXM016(S.Y.)from the Chongqing Science and Health Joint Fund. 摘　　要：The inhibitory receptor signal regulatory protein-α(Sirpα)is a myeloid-specific immune checkpoint that engages the“don’t eat me”signal CD47,which is expressed on tumor and normal tissue cells.However,the profile and regulatory mechanism of Sirpαexpression in tumor-associated macrophages(TAMs)are still not clear.Here,we found that the expression of Sirpαin TAMs increased dynamically with colorectal cancer(CRC)progression.Mechanistically,CRC cell-derived lactate induced the nuclear translocation of the transcription factor Ap-2αfrom the cytoplasm in TAMs.Ap-2αfunctioned as a transcription factor for Elk-1 by binding to the conserved element GCCTGC located at−1396/−1391 in the mouse Elk-1 promoter.Subsequently,the Elk-1 protein bound to two conserved sites,CTTCCTACA(located at−229/−221)and CTTCCTCTC(located at−190/−182),in the mouse Sirpαpromoter and promoted Sirpαexpression in TAMs.Functionally,the macrophage-specific knockout of Ap-2αnotably promoted the phagocytic activity of TAMs and suppressed CRC progression,whereas these effects were prevented by the transgenic macrophage-specific expression of Elk-1,which regulated TAM phagocytosis and CRC development in a Sirpα-dependent manner.Furthermore,we showed that Elk-1 expression was positively correlated with Sirpαexpression in TAMs and was associated with poor survival in CRC patients.Taken together,our findings revealed a novel mechanism through which CRC evades innate immune surveillance and provided potential targets for macrophage-based immunotherapy for CRC patients. 关 键 词：COLORECTAL cancer promoted
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