期刊
HEPATOLOGY
卷 75, 期 6, 页码 1402-1419出版社
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1002/hep.32232
关键词
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资金
- National Key Technologies RD Program [2018YFC1106800]
- National Natural Science Foundation of China [82173248, 81972747, 81972204, 81872004, 81800564, 81770615, 81702327, 81700555, 81672882]
- Science and Technology Support Program of Sichuan Province [2019YFQ0001, 2018SZ0115, 2017SZ0003]
- Science and Technology Program of Tibet Autonomous Region [XZ201801-GB-02]
- 1.3.5 project for disciplines of excellence, West China Hospital, Sichuan University [ZYJC18008]
Our study demonstrates that cGGNBP2-184aa, a protein encoded by IL-6-induced cGGNBP2, forms a positive feedback loop to facilitate ICC progression and may serve as an auxiliary target for clinical IL-6/STAT3-targeting treatments in ICC.
Background and Aims IL-6-induced tumor progression has been well established through the induction of antiapoptotic and proliferative genes. However, whether other mechanisms such as IL-6 regulation of circular RNAs (circRNAs) may also contribute to tumor development remains unknown. Approach and Results High-throughput RNA sequencing was used to identify the differentially expressed circRNAs on IL-6 stimulation in intrahepatic cholangiocarcinoma (ICC) cells. CircRNA GGNBP2 (derived from ggnbp2 gene, termed as cGGNBP2) was up-regulated by IL-6 treatment in a time and concentration-dependent manner. The biogenesis of cGGNBP2 was regulated by RNA-binding protein DEx-H Box Helicase 9, which was also mediated by IL-6 exposure. Mass spectrometry and western blotting identified a protein cGGNBP2-184aa encoded by cGGNBP2. cGGNBP2-184aa promoted ICC cell proliferation and metastasis in vitro and in vivo. Mechanistically, cGGNBP2-184aa directly interacted with signal transducers and activators of transduction-3 (STAT3), phosphorylated STAT3(Tyr705), and played a positive regulatory role in modulating IL-6/STAT3 signaling. IL-6/cGGNBP2-184aa/STAT3 formed a positive feedback loop to sustain constitutive activation of IL-6/STAT3 signaling. Elevated cGGNBP2 expression was correlated with poor prognosis of patients with ICC and was identified as an independent risk factor for patient prognosis. Conclusions Our study demonstrates that cGGNBP2-184aa, a protein encoded by IL-6-induced cGGNBP2, formed a positive feedback loop to facilitate ICC progression and may serve as an auxiliary target for clinical IL-6/STAT3-targeting treatments in ICC.
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