CircIL4R facilitates the tumorigenesis and inhibits ferroptosis in hepatocellular carcinoma by regulating the miR-541-3p/GPX4 axis.

Ferroptosis is a specific iron-dependent cell death form that can induce the production of lipid peroxide, but the roles of circular RNAs (circRNAs) in ferroptosis are completely unaware. Circ-interleukin-4 receptor (circIL4R) was reported to express highly in hepatocellular carcinoma (HCC). This study focused on the function of circIL4R dysregulation in tumor progression and ferroptosis of HCC, as well as its molecular mechanism. The quantitative real-time polymerase chain reaction was implemented for measuring RNA expression. Cell proliferation and survival were evaluated using 3-(4,5-dimethylthiazol-2-y1)-2,5-diphenyl tetrazolium bromide. Apoptotic cells were detected via flow cytometry. The quantification of protein expression was executed through western blotting analysis. The target binding was assessed via the dual-luciferase reporter, RNA immunoprecipitation, and RNA pull-down assays. The experiment in vivo was performed using a xenograft model. CircIL4R was abnormally overexpressed in HCC tissues and cells. CircIL4R knockdown impeded oncogenesis and expedited ferroptosis of HCC cells. CircIL4R could directly sponge microRNA-541-3p (miR-541-3p) and miR-541-3p inhibition mitigated the effects of circIL4R knockdown on HCC cells. CircIL4R acted as a miR-541-3p sponge to regulate its target glutathione peroxidase 4 (GPX4). GPX4 upregulation relieved the miR-541-3p-induced tumor inhibition and ferroptosis aggravation. CircIL4R played an oncogenic role in HCC via the miR-541-3p/GPX4 axis in vivo. Our data suggested that circIL4R served for a tumor promoter and ferroptosis inhibitor in HCC by the miR-541-3p/GPX4 network.

Xu Q ，Zhou L ，Yang G ，Meng F ，Wan Y ，Wang L ，Zhang L ... -  《-》

Circular RNA 0016142 Knockdown Induces Ferroptosis in Hepatocellular Carcinoma Cells via Modulation of the MicroRNA-188-3p/Glutathione Peroxidase 4 Axis.

Hepatocellular carcinoma (HCC) has high incidence and mortality rates, and it is characterized by invasiveness, poor prognosis, and limited treatment opportunities. The objective of our research was to assess the role of circ_0016142 in HCC. The ferroptosis inducer RSL3 and the iron chelator deferoxamine were used to treat cells to induce or inhibit ferroptosis, respectively, and cell viability and proliferation were assessed in Hep3B and HA22T cells by CCK8 and EdU assays, respectively. ROS, MDA, GSH, and Fe2+ levels were determined using commercial kits. RT-qPCR and western blotting were performed to determine the relative expression levels of entities of interest. Dual-luciferase reporter and RNA pull-down assays were performed to assess the relationship between circ_0016142/GPX4 and miR-188-3p. The results showed that circ_0016142/GPX4 was overexpressed, whereas miR-188-3p was downregulated in HCC. Circ_0016142 silencing reduced cell proliferation and GSH levels and increased ROS, MDA, and Fe2+ levels in HCC cells, and this was reversed by the miR-188-3p inhibitor. GPX4-overexpression abolished the effect of miR-188-3p mimic in HCC cells. In conclusion, circ_0016142 silencing suppressed HCC cell proliferation by inducing ferroptosis via the miR-188-3p/GPX4 axis.

Liu Y ，Li J 《-》

PART1 facilitates tumorigenesis and inhibits ferroptosis by regulating the miR-490-3p/SLC7A11 axis in hepatocellular carcinoma.

Li D ，Wan M ，Liu X ，Ojha SC ，Sheng Y ，Li Y ，Sun C ，Deng C ... -  《Aging-US》

HuR-induced circ_0082319 contributes to hepatocellular carcinoma by elevating PTK2 through miR-505-3p.

The aim of the present research is to explore the biological function and mechanism of circ_0082319 in HCC progression. Circ_0082319, microRNA-505-3p (miR-505-3p), protein tyrosine kinase 2 (PTK2), and human antigen R (HuR, also known as ELAVL1) level were detected by real-time quantitative polymerase chain reaction. Cell viability, proliferation, apoptosis, invasion, and angiogenesis were measured using (4-5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay, 5-ethynyl-2'-deoxyuridine (EdU), flow cytometry, transwell, and tube formation assays. Protein levels of c-Myc, MMP2, PTK2, and HuR were examined using western blot. The glycolysis levels were assessed using specific kits. Binding between miR-505-3p and circ_0082319 or PTK2 was predicted by Starbase and verified by a dual-luciferase reporter and RNA immunoprecipitation assays. The biological role of circ_0082319 on HCC tumor growth was examined using xenograft tumor model in vivo. Circ_0082319, PTK2, and HuR were highly expressed, and miR-505-3p was reduced in HCC samples and cell lines. Moreover, the knockdown of circ_0082319 might repress HCC cell proliferation, invasion, angiogenesis, and induce apoptosis in vitro. In mechanism, circ_0082319 served as a sponge of miR-505-3p to regulate PTK2 expression. HuR expedited circ_0082319 expression in HCC cells. HuR-mediated circ_0082319 might accelerate HCC cell proliferation, invasion, angiogenesis, and suppress apoptosis by the miR-505-3p/PTK2 axis, hinting at a promising therapeutic target for HCC treatment.

Qin C ，Liu S ，Chen W ，Xue D ，Guo T ，Wu B ... -  《-》

Ketamine Induces Ferroptosis of Liver Cancer Cells by Targeting lncRNA PVT1/miR-214-3p/GPX4.

Liver cancer ranks the top four malignant cancer type worldwide, which needs effective and safe treatment. Ferroptosis is a novel form of regulated cell death driven by iron-dependent lipid peroxidation and has been regarded as a promising therapeutic target for cancers. In this work, we aimed to study the effects of anesthetic ketamine on proliferation and ferroptosis of liver cancer. Cell viability and proliferation were detected by cell counting kit 8 (CCK-8), colony formation, and 5-ethynyl-2'-deoxyuridine (EdU) assay. Ferroptosis was determined by levels of Fe2+, lipid reactive oxygen species (ROS), and malondialdehyde (MDA). RNA levels of lncPVT1, miR-214-3p, and glutathione peroxidase 4 (GPX4) were checked by real-time PCR assay. Clinical liver tumor samples were collected to detect the levels of long noncoding RNA lncPVT1, miR-214-3p, and GPX4, and their correlation was evaluated by Pearson comparison test. Luciferase reporter gene assay and RNA pulldown were conducted to determine the binding between lncPVT1, miR-214-3p, and GPX4 3'UTR. Ketamine significantly suppressed viability and proliferation of liver cancer cells both in vitro and in vivo, as well as stimulated ferroptosis, along with decreased expression of lncPVT1 and GPX4. LncPVT1 directly interacted with miR-214-3p to impede its role as a sponge of GPX4. Depletion of lncPVT1 accelerated the ferroptosis of live cancer cells, whereas miR-214-3p inhibition and GPX4 overexpression reversed this effect. Ketamine-induced cell growth suppression and ferroptosis were also suppressed by miR-214-3p inhibition and GPX4 overexpression. In this work, we determined that ketamine suppressed viability of liver cancer cells and induced ferroptosis and identified the possible regulatory mechanism of lncPVT1/miR-214-3p/GPX4 axis.

He GN ，Bao NR ，Wang S ，Xi M ，Zhang TH ，Chen FS ... -  《Drug Design Development and Therapy》