Tumor Necrosis Factor a Reduces SNAP29 Dependent Autolysosome Formation to Increase Prion Protein Level and Promote Tumor Cell Migration  

作　　者：Huan Li Ren Wang Ze Yu Run Shi Jie Zhang Shanshan Gao Ming Shao Shuzhong Cui Zhenxing Gao Jiang Xu Man-Sun Sy Chaoyang Li 

机构地区：[1]Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430071,China [2]University of Chinese Academy of Sciences,Beijing 100000,China [3]Affiliated Cancer Hospital and Institute of Guangzhou Medical University,State Key Laboratory of Respiratory Disease,Guangzhou 510095,China [4]Department of Stomatology,First Affiliated Hospital,School of Medicine,Shihezi University,Shihezi 832008,China [5]Abdominal Surgery,Affiliated Cancer Hospital and Institute of Guangzhou Medical University,Guangzhou 510095,China [6]Department of Pathology,School of Medicine,Case Western Reserve University,Cleveland,OH 44106,USA

出　　处：《Virologica Sinica》2021年第3期458-475,共18页中国病毒学（英文版）

基　　金：supported by grants from the National Science Foundation of China (31670170 & 81560442);from MOST (2018YFA0507201);from the Natural Science Foundation of Guangdong Province (2017ZC0236)。

摘　　要：Tumor Necrosis Factor α(TNFα) is best known as a mediator of inflammation and immunity, and also plays important roles in tumor biology. However, the role of TNFα in tumor biology is complex and not completely understood. In a human melanoma cell line, M2, and a lung carcinoma cell line, A549, TNFα up-regulates prion protein(PrP) level, and promotes tumor cell migration in a PrP dependent manner. Silencing PRNP abrogates TNFα induced tumor cell migration;this phenotype is reversed when PRNP is re-introduced. Treatment with TNFα activates nuclear factor kappa B(NF-κB)signaling, which then mitigates autophagy by reducing the expression of Forkhead Box P3(FOXP3). Down regulation of FOXP3 reduces the transcription of synaptosome associated protein 29(SNAP29), which is essential in the fusion of autophagosome and lysosome creating autolysosome. FOXP3 being a bona fide transcription factor for SNAP29 is confirmed in a promoter binding assay. Accordingly, silencing SNAP29 in these cell lines also up-regulates PrP, and promotes tumor cell migration without TNFα treatment. But, when SNAP29 or FOXP3 is silenced in these cells, they are no longer respond to TNFα. Thus, a reduction in autophagy is the underlying mechanism by which expression of PrP is up-regulated,and tumor cell migration is enhanced upon TNFα treatment. Disrupting the TNFα-NF-κB-FOXP3-SNAP29 signaling axis may provide a therapeutic approach to mitigate tumor cell migration.

关 键 词：Tumor necrosis factorα(TNFα) Prion protein Synaptosome associated protein 29(SNAP29) Autophagy Nuclear factor kappa B(NF-κB) Forkhead box P3(FOXP3) 

分 类 号：R73-37[医药卫生—肿瘤]