EIF4A3-induced circTOLLIP promotes the progression of hepatocellular carcinoma via the miR-516a-5p/PBX3/EMT pathway

Author:

Liu Yachong,Song Jia,Zhang Hongwei,Liao Zhibin,Liu Furong,Su Chen,Wang Weijian,Han Mengzhen,Zhang Lu,Zhu He,Zhang Zhanguo,Liang Huifang,Zhang LeiORCID,Zhang Bixiang,Chen Xiaoping

Abstract

Abstract Background Circular RNAs (circRNAs) function as crucial regulators in multiple cancers, including hepatocellular carcinoma (HCC). However, the roles of circRNAs in HCC remains largely unknown. Methods circTOLLIP was identified in HCC by screening of two public circRNA microarray datasets and detected in HCC cells and tissues through quantitative real-time PCR (qRT–PCR) and in situ hybridization (ISH). Gain- and loss-of-function assays were performed to confirm the biological effects of circTOLLIP on HCC in vitro and in vivo. Mechanistically, bioinformatics analysis of online databases, MS2-RNA pulldown, biotin-labeled circTOLLIP/miR-516a-5p RNA pulldown, RNA immunoprecipitation (RIP), luciferase reporter assay, fluorescence in situ hybridization assay (FISH) and RNA sequencing were used to confirm the regulation of Eukaryotic initiation factor 4A3 (EIF4A3) on circTOLLIP and the interaction among circTOLLIP, miR-516a-5p and PBX homeobox 3 (PBX3). Results circTOLLIP was significantly upregulated in HCC cells and tissues. High circTOLLIP expression was correlated with poor overall survival (OS) and disease-free survival (DFS) in patients. circTOLLIP promoted the proliferation and metastasis of HCC cells in vitro and in vivo. Mechanistically, EIF4A3 promoted the biogenesis of circTOLLIP without affecting its stability. Moreover, circTOLLIP sponged miR-516a-5p to elevate the expression of PBX3, thereby activating the epithelial-to-mesenchymal transition (EMT) pathway and facilitating tumor progression in HCC. Conclusions Our findings indicate that EIF4A3-induced circTOLLIP promotes the progression of HCC through the circTOLLIP/miR-516a-5p/PBX3/EMT axis.

Funder

National Natural Science Foundation of China

Hepatobiliary and Pancreatic Cancer from Hubei Chen Xiaoping Foundation for Scientific and Technological Development

Start Up Fund for Returnees from Tongji Hospital

Shanxi Province“136” Revitalization Medical Project Construction Funds.

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Oncology

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