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

doi:10.1016/j.isci.2023.108022

N6-methyladenosine modification promotes hepatocarcinogenesis through circ-CDYL-enriched and EpCAM-positive liver tumor-initiating exosomes

iScience. 2023 Oct 13;26(10):108022. doi: 10.1016/j.isci.2023.108022. eCollection 2023 Oct 20.

Authors

Yanping Wei^{1

2}, Jingbo Fu^{1

2}, Hailing Zhang³, Yan Ling⁴, Xuewu Tang^{5

2}, Shuowu Liu^{1

2}, Miao Yu^{1

2}, Fuyan Liu^{1

2}, Guokun Zhuang^{1

2}, Haihua Qian^{1

2}, Kecheng Zhang⁶, Pinhua Yang⁶, Xinwei Yang⁶, Qi Yang^{1

2}, Shennian Ge^{1

2}, Baohua Zhang⁶, Yexiong Tan^{1

2}, Liang Li^{1

2}, Hongyang Wang^{1

2

7}

Affiliations

¹ International Cooperation Laboratory on Signal Transduction, Eastern Hepato-biliary Surgery Institute, Second Military Medical University, Shanghai, China.
² National Center for Liver Cancer, Shanghai, China.
³ Changhai Hospital, Second Military Medical University, Shanghai, China.
⁴ Changzheng Hospital, Second Military Medical University, Shanghai, China.
⁵ Hepato-pancreato-biliary Center, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China.
⁶ Department of Biliary Tract Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China.
⁷ National Laboratory for Oncogenes and Related Genes, Cancer Institute, RenJi Hospital, Shanghai Jiao Tong University, Shanghai, China.

Abstract

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.

Keywords: Biological sciences; Cancer; Genetics; Molecular biology.