Related Experiment Video
Updated: Sep 11, 2025

In Vitro Cultivation Techniques for Modeling Liver Organogenesis, Building Assembloids, and Designing Synthetic Tissues using Human Cell Lines
Published on: April 18, 2025
m6A-Modified circRAPGEF1 Interaction with IGF2BP3 Promotes Hepatocellular Carcinoma Progression via Reprogramming
Juanyi Shi1,2,3, Sintim Mui1,2, Yongcong Yan1,2
1Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120, China.
Abstract:
Hepatocellular carcinoma (HCC) progression and therapy sensitivity are critically fueled by liver cancer stem cells (LCSCs), yet the regulatory mechanisms of circular RNAs (circRNAs) on LCSCs remain elusive. Here, through circRNA microarray analysis of LCSCs and non-stem HCC cells, circRAPGEF1 is identified as a LCSC-enriched circRNA upregulated in HCC tissues and predictive of poor patient survival. Functionally, circRAPGEF1 promoted the stemness properties, proliferation, and tumorigenicity of HCC cells. Mechanistically, the METTL3-mediated N6-methyladenosine (m6A) modification of circRAPGEF1 facilitated KH domain-dependent binding of IGF2BP3 to its UGGAC motif, which conferring stability to circRAPGEF1 while competitively disrupting the IGF2BP3/ASS1 mRNA interaction. This process led to the degradation of ASS1 mRNA, triggering aspartate accumulation and activation of the S6K/CAD signaling pathway. Crucially, circRAPGEF1 overexpression reduced the sorafenib sensitivity, whereas targeting circRAPGEF1 using nanoparticles-mediated systematic siRNAs delivery effectively sensitized HCC cells to sorafenib. Collectively, these findings unveil a METTL3/circRAPGEF1/IGF2BP3/ASS1 regulatory axis that drives aspartate metabolic reprogramming to fuel HCC stemness properties, positioning circRAPGEF1 as a dual prognostic biomarker and therapeutic target to enhance sorafenib efficacy in HCC.
More Related Videos
Related Concept Videos
mTOR Signaling and Cancer Progression
The mTOR pathway or the...
Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
PI3K/mTOR/AKT Signaling Pathway
Abnormal Proliferation
Mitogens and the Cell Cycle
TGF - β Signaling Pathway

