A novel circular RNA circ-LRIG3 facilitates the malignant progression of hepatocellular carcinoma by modulating the EZH2/STAT3 signaling

作者：Suofeng Sun, Jing Gao, Shen Zhou, Yuan Li, Yu Wang, Li Jin, Jian Li, Bowei Liu, Bingyong Zhang, Shuangyin Han, Hui Ding, Xiuling Li · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2020 · DOI：10.1186/s13046-020-01779-5 · 被引用次数：91 · 研究领域：Circular RNAs in diseases、Cancer Mechanisms and Therapy、Ferroptosis and cancer prognosis

BACKGROUND: Circular RNA (circRNA) is emerging as an important player in human diseases, especially cancer. In our previous study, we identified a series of deregulated circRNAs in hepatocellular carcinoma (HCC) by performing circRNA microarray expression profile. Here, we aimed to explore the role of circ-LRIG3 (hsa_circ_0027345) in HCC. METHODS: qRT-PCR and western blot were used to asses gene and protein expression, respectively. CCK-8, EdU and Transwell assays were used to detect cell proliferation, migration and invasion. GSEA software was applied to analyze the pathway related to circ-LRIG3. Co-IP, RIP and ChIP assays were used to identify the positive feedback axis of circ-LRIG3/EZH2/STAT3. Animal study was carried to test the role of circ-LRIG3 in vivo. RESULTS: Circ-LRIG3 was notably upregulated in HCC and promoted HCC cell proliferation, migration, invasion and reduced apoptosis. Circ-LRIG3 formed a ternary complex with EZH2 and STAT3, facilitating EZH2-induced STAT3 methylation and subsequent phosphorylation, resulting in the activation of STAT3 signaling. In turn, activated STAT3 could directly bind to circ-LRIG3 promoter to increase circ-LRIG3 transcription activity, thus forming a positive feedback loop. The animal models showed that exogenous expression of circ-LRIG3 enhanced tumorigenicity and metastasis in vivo, whereas these effects were blocked after treatment with C188-9, a specific STAT3 small-molecule inhibitor. Clinically, high circ-LRIG3 was closely li...