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

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

  • J Exp Clin Cancer Res. 2020 Nov 23;39(1):252. doi: 10.1186/s13046-020-01779-5.
Suofeng Sun 1 2 Jing Gao 1 Shen Zhou 1 Yuan Li 3 Yu Wang 1 4 Li Jin 5 Jian Li 1 Bowei Liu 1 Bingyong Zhang 1 Shuangyin Han 1 Hui Ding 6 Xiuling Li 7
Affiliations

Affiliations

  • 1 Department of GastroenterologyHenan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, 450003, Henan, China.
  • 2 Department of Microbiome Laboratory, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou, China.
  • 3 Department of Traditional Chinese Medicine, The Third Affiliated Hospital Affiliated of Henan University of Traditional Chinese Medicine, Zhengzhou, 450003, Henan, China.
  • 4 Xinxiang Medical University, Xinxiang, 453000, Henan, China.
  • 5 Xinxiang aviation industry (Group) Co., Ltd. Hospital, Xinxiang, 453000, Henan, China.
  • 6 Department of GastroenterologyHenan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, 450003, Henan, China. dinghui76sy@163.com.
  • 7 Department of GastroenterologyHenan Provincial People's Hospital, People's Hospital of Zhengzhou University, School of Clinical Medicine, Henan University, Zhengzhou, 450003, Henan, China. zzlixiuling@aliyun.com.
Abstract

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 linked with aggressive clinicopathological features and was identified as an independent risk prognostic factor of overall survival. Importantly, plasma circ-LRIG3 was found to be a highly sensitive and specific non-invasive diagnostic indicator for HCC.

Conclusions: Our study reveals the carcinogenic role of circ-LRIG3 in HCC, which may provide a new therapeutic target for HCC patients.

Keywords

Biomarker; Circular RNA; Hepatocellular carcinoma; Molecular interaction; STAT3 signaling.

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