A N7-methylguanosine modified circular RNA, circIPP2A2, promotes malignant behaviors in hepatocellular carcinoma by serving as a scaffold in modulating the Hornerin/PI3K/AKT/GSK3β axis.
Zeyi Guo, Zhongzhe Li, Jinhao Guo, Luxiang Gan, Haiyu Mo, Jiajun Zhang, Yu Fu, Yi Wang, Meixian Jin, Yanping Wu, Qingyu Xie, Kunjiang Tan, Chunming Wang, Yuyan Xu, Guolin He, Lei Cai, Yi Gao, Mingxin Pan, Shunjun Fu
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引用次数: 0
Abstract
Despite the advancements in treatment strategies, the long-term survival of hepatocellular carcinoma (HCC) is still pessimistic. Therefore, understanding the mechanisms of hepatocellular carcinoma may offer substantial benefits for patients. Our previous research has revealed that Hornerin promoted HCC progression by regulating the AKT signaling pathway. To investigate the upstream regulatory mechanism, the results from RNA Immunoprecipitation and RNA pull-down indicated that the specific region of circIPP2A2 interacted with Hornerin. Additionally, patients with circIPP2A2 upregulation exhibited a poorer survival outcome following surgery compared to the cases with downregulated circIPP2A2. After the structure verification of circIPP2A2, loss-of-function studies using a lentiviral vector revealed that circIPP2A2 downregulation significantly inhibited HCC tumorigenesis and progression both in vitro and in vivo. Mechanistically, the m7G-MeRIP results demonstrated significant enrichment of circIPP2A2. Subsequent studies validated that METTL1 influenced the stability of circIPP2A2 and its binding affinity with Hornerin. Immunoprecipitation and immunofluorescence indicated that circIPP2A2 served as a molecular scaffold to facilitate Hornerin to interact with PI3K. In conclusion, our findings reveal that circIPP2A2, regulated by N7-methylguanosine modification, promotes malignant behaviors in HCC by serving as a molecular scaffold in modulating the Hornerin/PI3K/AKT/GSK3β axis. Targeting circIPP2A2 may be a promising therapeutic strategy for patients with HCC.
期刊介绍:
Brought to readers by the editorial team of Cell Death & Differentiation, Cell Death & Disease is an online peer-reviewed journal specializing in translational cell death research. It covers a wide range of topics in experimental and internal medicine, including cancer, immunity, neuroscience, and now cancer metabolism.
Cell Death & Disease seeks to encompass the breadth of translational implications of cell death, and topics of particular concentration will include, but are not limited to, the following:
Experimental medicine
Cancer
Immunity
Internal medicine
Neuroscience
Cancer metabolism