Abstract
BackgroundEpithelial-mesenchymal transition (EMT) has been associated with wound healing, tumorigenesis, and metastasis. Circular RNAs (circRNAs) are functional non-coding RNAs involved in multiple human cancers. However, whether and how circRNAs contribute to the EMT in hepatocellular carcinomas (HCC) remains to be deciphered. In this study, we investigated the regulation and function of hsa_circ_0003288 on programmed death-1 ligand 1 (PD-L1) during EMT and HCC invasiveness.MethodsHsa_circ_0003288 expression was measured by real-time quantitative reverse transcriptase PCR (qRT-PCR). Luciferase reporter assays, RNA pull-down assay and fluorescence in situ hybridization (FISH) were used to determine the correlation between hsa_circ_0003288 and miR-145 and between miR-145 and PD-L1. Furthermore, ectopic overexpression and siRNA-mediated downregulation of hsa_circ_0003288, transwell assays, and in vivo studies were used to determine the function of hsa_circ_0003288 on the EMT and invasiveness of L02 and HCC cells.ResultsmiR-145 directly targeted the PD-L1 3′-untranslated region (UTR) region, and hsa_circ_0003288 acted as a miR-145 sponge to regulate PD-L1 expression. Overexpression of hsa_circ_0003288 increased PD-L1 levels and promoted EMT, migration, and invasiveness of L02 cells. These observations were reversed after knockdown of hsa_circ_0003288 in HepG2 and Huh7 cells. Overexpression of PD-L1 rescued EMT, migration, and invasiveness of HepG2 and Huh7 cells after knockdown of hsa_circ_0003288. Furthermore, hsa_circ_0003288 knockdown reduced EMT in in vivo studies. Hsa_circ_0003288/PD-L1 axis was found to mediate the metastatic phenotypes via the PI3K/Akt pathway in HCC. Additionally, expression levels of hsa_circ_0003288 were increased and positively correlated with PD-L1 expression in HCC tissues.ConclusionOur findings demonstrated that hsa_circ_0003288 promoted EMT and invasion of HCC via the hsa_circ_0003288/miR-145/PD-L1 axis through the PI3K/Akt pathway. Targeting hsa_circ_0003288 may be a therapeutic strategy for the treatment of HCC.
Highlights
Epithelial-mesenchymal transition (EMT) has been associated with wound healing, tumorigenesis, and metastasis
Our results demonstrated that hsa_circ_0003288 expression was higher in hepatocellular carcinomas (HCC) cell lines compared to normal L02 cells (Fig. 1a)
Our results demonstrated that overexpression of miR-145 could reduce programmed death-1 ligand 1 (PD-L1) expression levels, while overexpression of hsa_circ_0003288 could prevent inhibition of PD-L1 expression in HepG2 and Huh7 cells (Fig. 4a–d)
Summary
Epithelial-mesenchymal transition (EMT) has been associated with wound healing, tumorigenesis, and metastasis. EMT plays an important role in tumor invasion. Epithelial-mesenchymal transition (EMT) plays an important role in cancer progression. During the EMT process, epithelial cancer cells lose their epithelial properties, such as cell polarity and intercellular adhesion, and gain mesenchymal properties, such as migration and invasion ability. EMT has been associated with drug resistance of targeted therapies [3, 4]. EMT is important for HCC metastasis and has been closely associated with patient survival. The development of sorafenib resistance in Huh cells may involve the PI3K/Akt signaling pathway. EMT is coordinated by multiple EMT-induced transcription factors (EMT-TFs) These transcription factors have been shown to be involved in stemness, immune escape, and drug resistance [7], such as ZEB1/2, SNAI1/2, and TWIST1/2 [8]
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