An HGF-dependent positive feedback loop between bladder cancer cells and fibroblasts mediates lymphangiogenesis and lymphatic metastasis  

作　　者：Yuting Li Hanhao Zheng Yuming Luo Yan Lin Mingjie An Yao Kong Yue Zhao Yina Yin Le Ai Jian Huang Changhao Chen 

机构地区：[1]Department of Oncology, Sun Yat-sen Memorial Hospital, Guangzhou, Guangdong, P. R. China [2]Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, P. R. China [3]Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, Guangdong, P. R. China [4]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 [5]Department of General Surgery, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, P. R. China

出　　处：《Cancer Communications》2023年第12期1289-1311,共23页癌症通讯（英文）

基　　金：funded by the National Key Research and Development Program of China(Grant No.2022YFA1305500 and 2018YFA0902803);the National Natural Science Foundation of China(Grant No.82173272,82173271,81825016,82103536,82103416,81871945 and 81902589);Guangdong Basic and Applied Basic Research Foundation(Grant No.2021B1515020091,2020A1515010815,2018B010109006,and 2021A1515010355);the Science and Technology Program of Guangzhou,China(Grant No.202002030388,201803010049,and 2017B020227007).

摘　　要：Background Cancer-associated fibroblasts (CAFs) play a vital role in facilitating tumor progression through extensive reciprocal interplay with cancer cells. Tumor-derived extracellular vesicles (EVs) are the critical mediators involved in the crosstalk between cancer cells and stromal cells, contributing to the metastasis of cancers. Yet, the biological mechanisms of tumor-derived EVs in triggering CAFs phenotype to stimulate the lymph node (LN) metastasis of bladder cancer (BCa) are largely unknown. Here, we aimed to explore the effects and molecular mechanisms of tumor-derived EV-mediated CAFs phenotype in regulating BCa LN metastasis. Methods The high-throughput sequencing was utilized to identify the crucial long non-coding RNA (lncRNA) associated with CAF enrichment in BCa. The functional role of the transition of fibroblasts to CAFs induced by LINC00665-mediated EVs was investigated through the in vitro and in vivo assays. Chromatin isolation by RNA purification assays, fluorescence resonance energy transfer assays, cytokine profiling and patient-derived xenograft (PDX) model were performed to explore the underlying mechanism of LINC00665 in the LN metastasis of BCa. Results We found that CAFs are widely enriched in the tumor microenvironment of BCa, which correlated with BCa lymphangiogenesis and LN metastasis. We then identified a CAF-associated long non-coding RNA, LINC00665, which acted as a crucial mediator of CAF infiltration in BCa. Clinically, LINC00665 was associated with LN metastasis and poor prognosis in patients with BCa. Mechanistically, LINC00665 transcriptionally upregulated RAB27B expression and induced H3K4me3 modification on the promoter of RAB27B through the recruitment of hnRNPL. Moreover, RAB27B-induced EVs secretion endowed fibroblasts with the CAF phenotype, which reciprocally induced LINC00665 overexpression to form a RAB27B-HGF-c-Myc positive feedback loop, enhancing the lymphangiogenesis and LN metastasis of BCa. Importantly, we demonstrated that blocking EV-transmitted LINC00665

关 键 词：bladder cancer Cancer-associated fibroblasts extracellular vesicles HGF LYMPHANGIOGENESIS lymph node metastasis long non-coding RNA positive feedback loop 

分 类 号：R737.14[医药卫生—肿瘤]