N6-methyladenosine modification promotes hepatocarcinogenesis through circ-CDYL-enriched and EpCAM-positive liver tumor-initiating exosomes
Yanping Wei,
Jingbo Fu,
Hailing Zhang,
Yan Ling,
Xuewu Tang,
Shuowu Liu,
Miao Yu,
Fuyan Liu,
Guokun Zhuang,
Haihua Qian,
Kecheng Zhang,
Pinhua Yang,
Xinwei Yang,
Qi Yang,
Shennian Ge,
Baohua Zhang,
Yexiong Tan,
Liang Li,
Hongyang Wang
Affiliations
Yanping Wei
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
Jingbo Fu
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
Hailing Zhang
Changhai Hospital, Second Military Medical University, Shanghai, China
Yan Ling
Changzheng Hospital, Second Military Medical University, Shanghai, China
Xuewu Tang
Hepato-pancreato-biliary Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China; National Center for Liver Cancer, Shanghai, China
Shuowu Liu
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
Miao Yu
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
Fuyan Liu
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
Guokun Zhuang
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
Haihua Qian
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
Kecheng Zhang
Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Pinhua Yang
Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Xinwei Yang
Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Qi Yang
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
Shennian Ge
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
Baohua Zhang
Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
Yexiong Tan
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China; Corresponding author
Liang Li
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China; Corresponding author
Hongyang Wang
International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China; National Laboratory for Oncogenes and Related Genes, Cancer Institute, RenJi Hospital, Shanghai Jiao Tong University, Shanghai, China; Corresponding author
Summary: CircRNAs play multiple roles in a variety of cellular processes. We found that Circ-CDYL is highly enriched in early HCC plasma exosomes. Moreover, EpCAM+ HCC cells and exosomes had significant Circ-CDYL levels. We postulated that Circ-CDYL-enriched and EpCAM-positive exosomes would function as liver tumor-initiating exosomes (LTi-Exos). As predicted, intercellular transfer of LTi-Exos activates the HDGF-PI3K-AKT-mTOR and HIF1AN-NOTCH2 axes in recipient cells, promoting malignancy. Upstream, we found that the N6-methyladenosine (m6A) modification of Circ-CDYL exerted its action in HCC cells through a dual mechanism. First, it stimulated back-splicing processes via YTHDC1 to promote Circ-CDYL biogenesis. Second, it facilitates the active sorting of Circ-CDYL into exosomes via hnRNPA2/B1. Clinically, the combination of LTi-Exos and plasma alpha-fetoprotein (AFP) provides a promising early diagnostic biomarker for HCC with an AUC of 0.896. This study highlights the effect and mechanism by which m6A modification promotes hepatocarcinogenesis via modulation of the tumor microenvironment by LTi-Exos.
