Tengfei Chen1, Yali Liu2, Chang Li1, Chun Xu1, Cheng Ding1, Jun Chen1, Jun Zhao3. 1. Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, Jiangsu, China. 2. Department of Pharmacology, Soochow University, Suzhou, 215000, China. 3. Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Medical College of Soochow University, Suzhou, Jiangsu, China. Electronic address: junzhao@suda.edu.cn.
Abstract
BACKGROUND: Exosomes in the tumor microenvironment (TME) facilitate tumor progression by enabling inter-cellular communication. Tumor cell-derived exosomes can polarize tumor-associated macrophages (TAMs) to an immunosuppressive M2 phenotype. The aim of this study was to determine the role of exosomal circFARSA in non-small cell lung cancer (NSCLC) and elucidate the underlying mechanisms. METHODS: In situ circFARSA expression in NSCLC tissues was analyzed using qRT-PCR. The in vitro migration of NSCLC cells was evaluated using a transwell assay or through indirect co-culture with M2 macrophages, as appropriate. Immunoprecipitation (IP), western blotting, RNA binding protein immunoprecipitation (RIP), and RNA pull down assays were conducted for mechanistic studies. RESULTS: CircFARSA was significantly upregulated in NSCLC tissues, and the ectopic overexpression of circFARSA enhanced NSCLC cell metastasis. Furthermore, NSCLC cell-derived exosomal circFARSA polarized the macrophages to a M2 phenotype. The NSCLC cells co-cultured with macrophages transfected with circFARSA or pre-treated with exosomal circFARSA showed enhanced EMT and metastasis. Mechanistically, exosomal circFARSA induced M2 polarization via PTEN ubiquitination and degradation, which further activated the PI3K/AKT signaling pathway. In addition, eIF4A3 promoted circRNA biogenesis and cyclization by binding to its flanking sequences. CONCLUSION: Exosomal circFARSA plays a crucial role in cross-talk between macrophages and NSCLC cells through the PTEN/PI3K/AKT signaling pathway, and is a promising diagnostic/prognostic biomarker for NSCLC.
BACKGROUND: Exosomes in the tumor microenvironment (TME) facilitate tumor progression by enabling inter-cellular communication. Tumor cell-derived exosomes can polarize tumor-associated macrophages (TAMs) to an immunosuppressive M2 phenotype. The aim of this study was to determine the role of exosomal circFARSA in non-small cell lung cancer (NSCLC) and elucidate the underlying mechanisms. METHODS: In situ circFARSA expression in NSCLC tissues was analyzed using qRT-PCR. The in vitro migration of NSCLC cells was evaluated using a transwell assay or through indirect co-culture with M2 macrophages, as appropriate. Immunoprecipitation (IP), western blotting, RNA binding protein immunoprecipitation (RIP), and RNA pull down assays were conducted for mechanistic studies. RESULTS: CircFARSA was significantly upregulated in NSCLC tissues, and the ectopic overexpression of circFARSA enhanced NSCLC cell metastasis. Furthermore, NSCLC cell-derived exosomal circFARSA polarized the macrophages to a M2 phenotype. The NSCLC cells co-cultured with macrophages transfected with circFARSA or pre-treated with exosomal circFARSA showed enhanced EMT and metastasis. Mechanistically, exosomal circFARSA induced M2 polarization via PTEN ubiquitination and degradation, which further activated the PI3K/AKT signaling pathway. In addition, eIF4A3 promoted circRNA biogenesis and cyclization by binding to its flanking sequences. CONCLUSION: Exosomal circFARSA plays a crucial role in cross-talk between macrophages and NSCLC cells through the PTEN/PI3K/AKT signaling pathway, and is a promising diagnostic/prognostic biomarker for NSCLC.
Authors: Bashdar Mahmud Hussen; Goran Sedeeq Hama Faraj; Mohammad Fatih Rasul; Hazha Jamal Hidayat; Abbas Salihi; Aria Baniahmad; Mohammad Taheri; Soudeh Ghafouri-Frad Journal: Cancer Cell Int Date: 2022-10-18 Impact factor: 6.429