SUMOylation-triggered ALIX activation modulates extracellular vesicles circTLCD4-RWDD3 to promote lymphatic metastasis of non-small cell lung cancer  

作　　者：Xiayao Diao Chao Guo Hanhao Zheng Ke Zhao Yuming Luo Mingjie An Yan Lin Jiancheng Chen Yuanlong Li Yuting Li Xuehan Gao Jiaqi Zhang Mengxin Zhou Wenliang Bai Lei Liu Guige Wang Lanjun Zhang Xiaotian He Rusi Zhang Zhihua Li Changhao Chen Shanqing Li 

机构地区：[1]Department of Thoracic Surgery,Peking Union Medical College Hospital,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing,P.R.China [2]Department of Urology,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [3]Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation,Sun Yat-sen Memorial Hospital,State Key Laboratory of Oncology in South China,Guangzhou,Guangdong,P.R.China [4]Department of General Surgery,Guangdong Provincial People’s Hospital,Guangdong Academy of Medical Sciences,Guangzhou,Guangdong,P.R.China [5]Cancer Center,Renmin Hospital of Wuhan University,Wuhan,Hubei,P.R.China [6]Department of Thoracic Surgery,Sun Yat-sen University Cancer Center,Sun Yat-sen University,Guangzhou,Guangdong,P.R.China [7]Department of Medical Oncology,Sun Yat-sen Memorial Hospital,Sun Yat-sen University,Guangzhou,Guangdong,P.R.China

出　　处：《Signal Transduction and Targeted Therapy》2023年第12期5887-5903,共17页信号转导与靶向治疗（英文）

基　　金：funded by the National High Level Hospital Clinical Research Funding(Grant No.2022-PUMCH-B-011);the National Key Research and Development Program of China(Grant No.2022YFA1305500);the National Natural Science Foundation of China(Grant No.32322023,82173272,81825016,82173230,82341018,82203662,82173271,82103416,82103536,82173266,82202276,and 81972385);the Key Areas Research and Development Program of Guangdong(Grant No.2022B1515120086,2021B1515020091,2022A1515140175,2021A1515010215,2023A1515011648,2022A1515012288,2021A1515010355);the Science and Technology Program of Guangzhou,China(Grant No.2023A04J2206).

摘　　要：Lymph node(LN)metastasis is one of the predominant metastatic routes of non-small cell lung cancer(NSCLC)and is considered as a leading cause for the unsatisfactory prognosis of patients.Although lymphangiogenesis is well-recognized as a crucial process in mediating LN metastasis,the regulatory mechanism involving lymphangiogenesis and LN metastasis in NSCLC remains unclear.In this study,we employed high-throughput sequencing to identify a novel circular RNA(circRNA),circTLCD4-RWDD3,which was significantly upregulated in extracellular vesicles(EVs)from LN metastatic NSCLC and was positively associated with deteriorated OS and DFS of patients with NSCLC from multicenter clinical cohort.Downregulating the expression of EV-packaged circTLCD4-RWDD3 inhibited lymphangiogenesis and LN metastasis of NSCLC both in vitro and in vivo.Mechanically,circTLCD4-RWDD3 physically interacted with hnRNPA2B1 and mediated the SUMO2 modification at K108 residue of hnRNPA2B1 by upregulating UBC9.Subsequently,circTLCD4-RWDD3-induced SUMOylated hnRNPA2B1 was recognized by the SUMO interaction motif(SIM)of ALIX and activated ALIX to recruit ESCRT-III,thereby facilitating the sorting of circTLCD4-RWDD3 into NSCLC cell-derived EVs.Moreover,EV-packaged circTLCD4-RWDD3 was internalized by lymphatic endothelial cells to activate the transcription of PROX1,resulting in the lymphangiogenesis and LN metastasis of NSCLC.Importantly,blocking EV-mediated transmission of circTLCD4-RWDD3 via mutating SIM in ALIX or K108 residue of hnRNPA2B1 inhibited the lymphangiogenesis and LN metastasis of NSCLC in vivo.Our findings reveal a precise mechanism underlying SUMOylated hnRNPA2B1-induced EV packaging of circTLCD4-RWDD3 in facilitating LN metastasis of NSCLC,suggesting that EV-packaged circTLCD4-RWDD3 could be a potential therapeutic target against LN metastatic NSCLC.

关 键 词：METASTASIS inhibited LYMPHATIC 

分 类 号：R734.2[医药卫生—肿瘤]