Circular RNA circDLC1 Inhibits MMP1-Mediated Liver Cancer Progression via Interaction with HuR

Abstract

Background: N6-methyladenosine (m6A) modification has been demonstrated to be closely related to cancer progression. KIAA1429, a key component of the m6A methyltransferase complex, has recently been reported to promote hepatocellular carcinoma (HCC) progression by regulating the m6A methylation. However, the involvement of circular RNAs (circRNAs) in KIAA1429-mediated HCC progression is still unknown.Methods: RNA sequencing (RNA-seq) and methylated RNA immunoprecipitation sequencing (m6A-seq) were utilized to identify KIAA1429-regulated circRNAs. The effects of circDLC1 on proliferation and metastasis of hepatoma cells were examined in vitro and in vivo. RT-qPCR was used to measure the expression of circDLC1 in HCC tissues and hepatoma cells. RNA FISH, RIP assays and biotin-labeled RNA pull-down were used to investigate the downstream effector of circDLC1. The downstream targets of circDLC1 were identified using RNA-seq.Results: Our data demonstrated that circDLC1 was downregulated in HCC tissues and closely relevant to favorable prognosis. Overexpression of circDLC1 inhibited the proliferation and motility of hepatoma cells in vitro and in vivo, while silencing of circDLC1 played the opposite role. Mechanistic investigations revealed that circDLC1 could bind to RNA-binding protein HuR, which subsequently reduced the interaction between HuR and MMP1 mRNAs, thus inhibited the expression of MMP1, finally contributed to inhibition of HCC progression.Conclusion: Our work suggests that circDLC1, a downstream target of KIAA1429, is a promising prognostic marker for HCC patients, and the circDLC1-HuR-MMP1 axis may serve as a potential therapeutic target for HCC treatment.

Comprehensive analysis of N6-methyladenosine -related long non-coding RNAs and immune cell infiltration in hepatocellular carcinoma

“…The results of our study are consistent with those reported by Liu et al in that an m6A-related gene inhibits matrix metalloproteinase mediated hepatocellular carcinoma progression on combination with Human antigen R [19]. Additionally, Zhou et al [20] indicated that m6A RNA methylation-mediated HNF3γ decreases HCC dedifferentiation and sorafenib resistance.…”

“…Furthermore, m6A modification influences liver carcinoma and lipid metabolism in hepatic disease as well as the potential therapeutic strategies. As a vital component of the m6A methyltransferase complex, circular RNAs (circRNAs) has been demonstrated recently to stimulate HCC progression [19]. m6A regulates HCC metastasis through a related signaling pathway and promotes incursive phenotypes by triggering epithelial-mesenchymal transition, which mediates the differentiation of HCC and drug resistance [20].…”

Circ-ZEB1 promotes PIK3CA expression by silencing miR-199a-3p and affects the proliferation and apoptosis of hepatocellular carcinoma

“…Cir-cRNAs participate in transcriptional regulation in the nucleus and compete with mRNA precursors during transcription [6,7]. Furthermore, these compete with mRNA for the targeted binding site of miRNA and ribosome entry sites, which can translate and express effective proteins [8][9][10]. Recently, high-throughput sequencing has revealed numerous circRNAs that are closely related to tumor progression.…”

The Mechanism and Clinical Significance of Circular RNAs in Hepatocellular Carcinoma

“…Meanwhile, the circRHOT1/Tip60/NR2F6 axis may partially activate the notch receptor 2 (NOTCH2) signaling pathway ( 58 ). β-catenin-370aa competitively interacts with glycogen synthase kinase 3β (GSK3β) and acts as a decoy, antagonizing GSK3β-induced β-catenin phosphorylation and degradation to stabilize full-length β-catenin, thereby activating the Wnt/β-catenin pathway to promote the malignant phenotypes of HCC ( 59 ). CircRNAs can also act as a tumor suppressor to inhibit the malignant biological behaviors of HCC.…”