Downregulation of HULC Induces Ferroptosis in Hepatocellular Carcinoma via Targeting of the miR-3200-5p/ATF4 Axis

Guan, Lulu; Wang, Feifei; Wang, Mengjiao; Han, Songfeng; Cui, Zhaohai; Xi, Shoumin; Xu, Haixu; Li, Shipeng

doi:10.1155/2022/9613095

Cited by 33 publications

(16 citation statements)

References 46 publications

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“…Inhibition of the expression of Slc7a11 could affect the activity of Gpx4, induce decline of GSH and accumulation of lipid ROS, and finally lead to ferroptosis [19]. Atf4, activating transcription factor 4, is a member of DNA-binding proteins that includes the AP-1 family of transcription factors, cAMP-response element binding proteins (CREBs) and CREB-like proteins [20][21][22][23]. Atf4 presented a protective role in oxidative stress and endoplasmic reticulum stress [24,25].…”

Section: Discussionmentioning

confidence: 99%

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Miao

Wang

Zeng

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. Sevoflurane is one of the most popular inhalational anesthetics during perioperative period but presenting neurotoxicity among pediatric and aged populations. Recent experiments in vivo and in vitro have indicated that ferroptosis may contribute to the neurotoxicity of sevoflurane anesthesia. However, the exact mechanism is still unclear. Methods. In current study, we explored the differential expressed genes (DEGs) in HT-22 mouse hippocampal neuronal cells after sevoflurane anesthesia using RNA-seq. Differential expressed ferroptosis-related genes (DEFRGs) were screened and analyzed by Gene Ontology (GO) and pathway enrichment analysis. Protein-to-protein interaction (PPI) network was constructed by the Search Tool for the Retrieval of Interacting Genes (STRING). Significant modules and the hub genes were identified by using Cytoscape. The Connectivity Map (cMAP) was used for screening drug candidates targeting the identified DEFRGs. Potential TF-gene network and drug-gene pairs were established towards the hub genes. In final, we validated these results in experiments. Results. A total of 37 ferroptosis-related genes (18 upregulated and 19 downregulated) after sevoflurane exposure in hippocampal neuronal cells were finally identified. These differentially expressed genes were mainly involved into the biological processes of cellular response to oxidative stress. Pathway analysis indicated that these genes were involved in ferroptosis, mTOR signaling pathway, and longevity-regulating pathway. PPI network was constructed. 10 hub genes including Prkaa2, Chac1, Arntl, Tfrc, Slc7a11, Atf4, Mgst1, Lpin1, Atf3, and Sesn2 were found. Top 10 drug candidates, gene-drug networks, and TFs targeting these genes were finally identified. These results were validated in experiments. Conclusion. Our results suggested that ferroptosis-related genes play roles in sevoflurane anesthesia-related hippocampal neuron injury and offered the hub genes and potential therapeutic agents for investigating and treatment of this neurotoxicity after sevoflurane exposure. Finally, therapeutic effect of these drug candidates and function of potential ferroptosis targets should be further investigated for treatment and clarifying mechanisms of sevoflurane anesthesia-induced neuron injury in future research.

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Section: Discussionmentioning

confidence: 99%

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Miao

Wang

Zeng

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…To date, extensive evidence has shown that lncRNAs could act as a molecular sponge for miRNAs in cancers via the ceRNA mechanism to modulate ferroptosis. For example, lncRNAs HULC in HCC induced ATF4 stability by competitively binding to miR-3200-5p, resulting in the inhibition of ferroptosis ( Guan et al, 2022 ). Among these lncRNAs, we found that nine possible lncRNAs in HCC were screened through the starBase database, and the high activity of both DUXAP8 and LINC00511 within HCC had poorer survival outcomes.…”

Section: Discussionmentioning

confidence: 99%

Integrative analyses of prognosis, tumor immunity, and ceRNA network of the ferroptosis-associated gene FANCD2 in hepatocellular carcinoma

Yang

Song²,

Li³

et al. 2022

Front. Genet.

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Extensive evidence has revealed that ferroptosis plays a vital role in HCC development and progression. Fanconi anemia complementation group D2 (FANCD2) has been reported to serve as a ferroptosis-associated gene and has a close relationship with tumorigenesis and drug resistance. However, the impact of the FANCD2-related immune response and its mechanisms in HCC remains incompletely understood. In the current research, we evaluated the prognostic significance and immune-associated mechanism of FANCD2 based on multiple bioinformatics methods and databases. The results demonstrated that FANCD2 was commonly upregulated in 15/33 tumors, and only the high expression of FANCD2 in HCC was closely correlated with worse clinical outcomes by OS and DFS analyses. Moreover, ncRNAs, including two major types, miRNAs and lncRNAs, were closely involved in mediating FANCD2 upregulation in HCC and were established in a ceRNA network by performing various in silico analyses. The DUXAP8-miR-29c-FANCD2 and LINC00511-miR-29c-FANCD2 axes were identified as the most likely ncRNA-associated upstream regulatory axis of FANCD2 in HCC. Finally, FANCD2 expression was confirmed to be positively related to HCC immune cell infiltration, immune checkpoints, and IPS analysis, and GSEA results also revealed that this ferroptosis-associated gene was primarily involved in cancer-associated pathways in HCC. In conclusion, our investigations indicate that ncRNA-related modulatory overexpression of FANCD2 might act as a promising prognostic and immunotherapeutic target against HCC.

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“…miR-362-3p can promote the expression of MIOX and increase ferroptosis to alleviate the progression of liver cancer [45]. miR-3200-5p regulates liver cancer progression by targeting ATF4 to induce ferroptosis [46]. In recent years, several mediators involved in ferroptosis have been reported, including the accumulation of ROS, consumption of GSH, suppression of GPX4 activity, and elevated release of polyunsaturated fatty acids [47][48][49].…”

Section: Discussionmentioning

confidence: 99%

miR-21-5p Inhibits Ferroptosis in Hepatocellular Carcinoma Cells by Regulating the AKT/mTOR Signaling Pathway through MELK

et al. 2023

Journal of Immunology Research

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Background. Hepatocellular carcinoma (HCC) is one of the most prevalent cancers, and its incidence rate is increasing worldwide. At present, there is no ideal treatment for HCC. In recent years, molecular-targeted therapy has shown significant therapeutic benefits for patients. Ferroptosis is a modality of regulated cell death, and previous studies have found that inducing ferroptosis in liver cancer cells can inhibit the progression of liver cancer. The aim of this study is to investigate the regulatory mechanism of miR-21-5p in regulating ferroptosis in HCC cells. Methods. CCK-8 was used to measure cell viability, EdU and colony formation were used to measure cell proliferation, and Transwell assays were used to measure cell migration and invasion. RT-qPCR was used to detect the level of miR-21-5p, Western blotting was used to detect the protein expression level, a dual-luciferase reporter gene assay was used to determine the targeting relationship between miR-21-5p and MELK, and coimmunoprecipitation was used to determine the interaction between MELK and AKT. Results. Overexpression of miR-21-5p and MELK facilitated the viability, proliferation, colony formation, invasion, and migration of HCC cells. Downregulation of miR-21-5p suppressed the level of MELK and the progression of HCC. MELK regulated the AKT/mTOR signaling pathway, causing changes in the levels of GPX4, GSH, FTH1, xCT, heme oxygenase 1(HO-1), reactive oxygen species, and Fe2+ to regulate the ferroptosis of hepatoma cells. Erastin, an inducer of ferroptosis, attenuated the repressive influence of miR-21-5p on ferroptosis in HCC cells. Conclusion. In summary, this study demonstrates that miR-21-5p inhibits the ferroptosis of HCC cells by regulating the AKT/mTOR signaling pathway through MELK.

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Downregulation of HULC Induces Ferroptosis in Hepatocellular Carcinoma via Targeting of the miR-3200-5p/ATF4 Axis

Cited by 33 publications

References 46 publications

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Identification and Validation of Ferroptosis-Related Genes in Sevoflurane-Induced Hippocampal Neurotoxicity

Integrative analyses of prognosis, tumor immunity, and ceRNA network of the ferroptosis-associated gene FANCD2 in hepatocellular carcinoma

miR-21-5p Inhibits Ferroptosis in Hepatocellular Carcinoma Cells by Regulating the AKT/mTOR Signaling Pathway through MELK

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