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.
Yanping Wei  1  2 ,  Jingbo Fu  1  2 ,  Hailing Zhang  3 ,  Yan Ling  4 ,  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 Zhang  6 ,  Pinhua Yang  6 ,  Xinwei Yang  6 ,  Qi Yang  1  2 ,  Shennian Ge  1  2 ,  Baohua Zhang  6 ,  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.
PMID: 37954137 DOI: 10.1016/j.isci.2023.108022
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.
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