Circ-RAPGEF5 promotes intrahepatic cholangiocarcinoma progression by stabilizing SAE1 to facilitate SUMOylation.

Junhao Zheng, Yali Wang, Liye Tao, Jingwei Cai, Zefeng Shen, Yang Liu, Haoyu Pan, Shihao Li, Yeling Ruan, Tianyi Chen, Zhengtao Ye, Kainan Lin, Yin Sun, Junjie Xu, Xiao Liang

Journal of experimental & clinical cancer research : CR 2023 Sep 13

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Intrahepatic cholangiocarcinoma (ICC) is an aggressive malignancy with a poor prognosis. The underlying functions and mechanisms of circular RNA and SUMOylation in the development of ICC remain poorly understood. Circular RNA hsa_circ_0001681 (termed Circ-RAPGEF5 hereafter) was identified by circular RNA sequencing from 19 pairs of ICC and adjacent tissue samples. The biological function of Circ-RAPGEF5 in tumor proliferation and metastasis was examined by a series of in vitro assays. A preclinical model was used to validate the therapeutic effect of targeting Circ-RAPGEF5. RNA pull-down and dual-luciferase reporter assays were used to access the RNA interactions. Western blot and Co-IP assays were used to detect SUMOylation levels. Circ-RAPGEF5, which is generated from exons 2 to 6 of the host gene RAPGEF5, was upregulated in ICC. In vitro and in vivo assays showed that Circ-RAPGEF5 promoted ICC tumor proliferation and metastasis, and inhibited apoptosis. Additionally, high Circ-RAPGEF5 expression was significantly correlated with a poor prognosis. Further investigation showed that SAE1, a potential target of Circ-RAPGEF5, was also associated with poor oncological outcomes. RNA pull-down and dual-luciferase reporter assays showed an interaction of miR-3185 with Circ-RAPGEF5 and SAE1. Co-IP and western blot assays showed that Circ-RAPGEF5 is capable of regulating SUMOylation. Circ-RAPGEF5 promotes ICC tumor progression and SUMOylation by acting as a sponge for miR-3185 to stabilize SAE1. Targeting Circ-RAPGEF5 or SAE1 might be a novel diagnostic and therapeutic strategy in ICC. © 2023. Italian National Cancer Institute ‘Regina Elena’.

Citation

Junhao Zheng, Yali Wang, Liye Tao, Jingwei Cai, Zefeng Shen, Yang Liu, Haoyu Pan, Shihao Li, Yeling Ruan, Tianyi Chen, Zhengtao Ye, Kainan Lin, Yin Sun, Junjie Xu, Xiao Liang. Circ-RAPGEF5 promotes intrahepatic cholangiocarcinoma progression by stabilizing SAE1 to facilitate SUMOylation. Journal of experimental & clinical cancer research : CR. 2023 Sep 13;42(1):239