<p>Exosomal Circ-ZNF652 Promotes Cell Proliferation, Migration, Invasion and Glycolysis in Hepatocellular Carcinoma via miR-29a-3p/GUCD1 Axis</p>

Abstract

Background: Circular RNAs (circRNAs) play a crucial role in hepatocellular carcinoma (HCC) progression. However, the role of exosomal circRNAs in HCC is still largely unknown. We aimed to explore the function of exosomal circ-ZNF652 in HCC. Methods: The morphology and size of exosomes were examined by transmission electron microscopy (TEM) and nanoparticle tracking analysis (NTA). The expression of circ-ZNF652, ZNF652 mRNA, microRNA-29a-3p (miR-29a-3p) and guanylyl cyclase domain containing 1 (GUCD1) mRNA was determined by quantitative real-time polymerase chain reaction (qRT-PCR). The protein levels of CD63, CD81, hexokinase 2 (HK2) and GUCD1 were examined via Western blot assay. The stability of circ-ZNF652 was examined by RNase R digestion assay. Cell proliferation was analyzed by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Cell migration and invasion were assessed by transwell assay. The glycolysis level was detected via specific kits. The association between miR-29a-3p and circ-ZNF652 or GUCD1 was analyzed by dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay. A murine xenograft model was constructed to explore the effect of circ-ZNF652 in vivo. Results: Exosomal circ-ZNF652 was upregulated in HCC patients' serums and HCC cells. Exosomal circ-ZNF652 could transfer to HCC cells, and circ-ZNF652 silencing suppressed HCC cell proliferation, migration, invasion and glycolysis. Circ-ZNF652 was a sponge of miR-29a-3p, and the inhibitory effect of circ-ZNF652 silencing on HCC cell progression was weakened by miR-29a-3p inhibitor. GUCD1 was a target gene of miR-29a-3p, and GUCD1 overexpression restored the effect of miR-29a-3p on HCC cell development. Moreover, circ-ZNF652 knockdown repressed tumor growth in vivo. Conclusion: Exosomal circ-ZNF652 contributes to HCC cell proliferation, migration, invasion and glycolysis by miR-29a-3p/GUCD1 axis.

New Insights into the Role of miR-29a in Hepatocellular Carcinoma: Implications in Mechanisms and Theragnostics

“…Further validation approach confirmed that miR-29a directly targets SIRT1 to inhibit the proliferation and cell cycle progression of HCC [ 56 ]. Li et al showed that overexpression of miR-29a suppressed glycolytic phenotype to impede proliferation, migration, and invasion of HCC by targeting guanylyl cyclase domain containing 1 (GUCD1) [ 57 ]. In addition, the role of circRNA circ-ZNF652 in positively regulating miR-29a expression levels in HCC tumorigenicity was revealed [ 57 ].…”

“…Li et al showed that overexpression of miR-29a suppressed glycolytic phenotype to impede proliferation, migration, and invasion of HCC by targeting guanylyl cyclase domain containing 1 (GUCD1) [ 57 ]. In addition, the role of circRNA circ-ZNF652 in positively regulating miR-29a expression levels in HCC tumorigenicity was revealed [ 57 ]. More recently, Song et al demonstrated that miR-29a exerts HCC-counteracting effect by suppressing oncogene roundabout homolog 1 (Robo1) with direct binding at post-transcriptional level [ 58 ].…”

Circulating Long and Circular Noncoding RNA as Non-Invasive Diagnostic Tools of Hepatocellular Carcinoma

“…Further examination on the exosome-enriched fraction (30–150 nm) showed that the levels of LINC00161 were upregulated in patients with HCC in contrast to controls ( p < 0.05). No statistical significance was detected for the expression of LINC00161 in HCC urine and serum exosome-free samples compared with controls [ 99 ]. Previously, LINC00161 was shown to be expressed significantly higher in HCC tissues and its high expression was related to a poor prognosis [ 119 ].…”

“…Despite the work from Li [ 99 ] being focused on the identification of the molecular effects derived from the transfer of exosomal circ-ZNF652 in cancer recipient cells, where the miR-29a-3p sponging promoted proliferation, migration, invasion, and glycolysis by affecting the guanylyl cyclase domain containing 1 (GUCD1) expression, it provided also evidence of circ-ZNF652 being higher in exosomes collected from cancer patients, compared to controls [ 99 ]. However, this evidence was derived from the analysis of 33 HCC samples and no further investigation of its diagnostic or prognostic potential was conducted.…”

Circular RNAs Sparkle in the Diagnosis and Theranostics of Hepatocellular Carcinoma

“…The expression of circRNA_100338 is positively correlated with poorer of OS and PFS of HCC patients ( Huang et al, 2017 ). circ_0005075 promotes HCC progression via miR-431 ( Li et al, 2018 ), and exosomal circ-ZNF652 could transfer to HCC cells to promote cell proliferation, migration, invasion, and glycolysis in HCC via the miR-29a-3p/GUCD1 axis ( Li Y. et al, 2020 ). CircMAST1 elicits HCC progression by sponging miRNA-1299 and stabilizing CTNND1.…”