Role of ferroptosis in hepatocellular carcinoma

Nie, Jianhua; Lin, Binlin; Zhou, Meng; Wu, Li Hua; Zheng, Tongsen

doi:10.1007/s00432-018-2740-3

Cited by 183 publications

(166 citation statements)

References 54 publications

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“…These regulatory factors can inhibit ferroptosis in HCC cells in different ways. The p62-Keap1-NRF2 pathway plays an important role in preventing ferroptosis in HCC cells, and the RAS/Raf/MEK pathway is an important target for the treatment of HCC 32,40 . MT-1G promotes the development of sorafenib resistance by inhibiting ferroptosis, and MT-1G knockdown increases GSH depletion and lipid peroxidation 41 .…”

Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

Ferroptosis: past, present and future

et al. 2020

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Ferroptosis is a new type of cell death that was discovered in recent years and is usually accompanied by a large amount of iron accumulation and lipid peroxidation during the cell death process; the occurrence of ferroptosis is iron-dependent. Ferroptosis-inducing factors can directly or indirectly affect glutathione peroxidase through different pathways, resulting in a decrease in antioxidant capacity and accumulation of lipid reactive oxygen species (ROS) in cells, ultimately leading to oxidative cell death. Recent studies have shown that ferroptosis is closely related to the pathophysiological processes of many diseases, such as tumors, nervous system diseases, ischemia-reperfusion injury, kidney injury, and blood diseases. How to intervene in the occurrence and development of related diseases by regulating cell ferroptosis has become a hotspot and focus of etiological research and treatment, but the functional changes and specific molecular mechanisms of ferroptosis still need to be further explored. This paper systematically summarizes the latest progress in ferroptosis research, with a focus on providing references for further understanding of its pathogenesis and for proposing new targets for the treatment of related diseases. Facts Ferroptosis is a new type of programmed cell death, which occurs with iron dependence. Ferroptosis plays an important regulatory role in the occurrence and development of many diseases, such as tumors, neurological diseases, acute kidney injury, ischemia/reperfusion, etc. Activating or blocking the ferroptosis pathway to alleviate the progression of the disease, which provides a promising therapeutic strategy for many diseases. Open questions What is the relationship between ferroptosis and other types of cell death? Is it synergy or antagonism? Is iron necessary to promote the production of lipid peroxides, or can other substances take the place of iron in ferroptosis? What is the downstream regulation mechanism of iron in ferroptosis? How can ferroptosis promote the development of inflammation?

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Section: Hepatocellular Carcinoma (Hcc)mentioning

confidence: 99%

Ferroptosis: past, present and future

et al. 2020

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“…Small compounds, such as erastin, Ras‐selective lethal small molecule 3 (RSL3), RSL5, and some drugs, such as sorafenib and artesunate (Xie et al, 2016) have been identified as ferroptosis inducers due to their ability to induce iron‐dependent accumulation of lipid reactive oxygen species (ROS; Dixon et al, 2012). These ferroptosis inducers exert antitumor activities in many types of malignancies (Dachert, Schoeneberger, Rohde, & Fulda, 2016; Sato et al, 2018; Shintoku et al, 2017), including HCC (Nie, Lin, Zhou, Wu, & Zheng, 2018; Sun et al, 2016). Although inducing ferroptosis is a promising anticancer strategy, the negative regulators of ferroptosis which inhibit cellular iron uptake and/or limit ROS production may hinder the application of ferroptosis inducers in anticancer therapy (Shen et al, 2018; Xie et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Small compounds, such as erastin, Ras-selective lethal small molecule 3 (RSL3), RSL5, and some drugs, such as sorafenib and artesunate (Xie et al, 2016) have been identified as ferroptosis inducers due to their ability to induce iron-dependent accumulation of lipid reactive oxygen species (ROS; Dixon et al, 2012). These ferroptosis inducers exert antitumor activities in many types of malignancies (Dachert, Schoeneberger, Rohde, & Fulda, 2016;Sato et al, 2018;Shintoku et al, 2017), including HCC (Nie, Lin, Zhou, Wu, & Zheng, 2018;Sun et al, 2016).…”

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confidence: 99%

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Bai

Liang

Zhu

et al. 2020

Journal Cellular Physiology

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Primary liver cancer is the second most frequent cause of cancer‐related deaths. Ferroptosis, a recognized form of regulated cell death, recently gains attention. MicroRNA‐214‐3p (miR‐214) plays a regulatory role in hepatocarcinogenesis. However, the role of miR‐214 in cellular ferroptosis is unclear. This study aimed at elucidating whether miR‐214 could regulate ferroptosis of liver cancer. In vitro, HepG2 and Hep3B cancer cells were treated with erastin, a ferroptosis inducer, and then erastin was demonstrated to suppress the cell viability. Moreover, pre‐miR‐214 overexpression caused that HepG2 and Hep3B cells were more susceptible to erastin, whereas anti‐miR‐214 sponge showed the opposite effect. Additionally, pre‐miR‐214 overexpression increased the malondialdehyde and reactive oxygen species levels, upregulated Fe2+ concentration, and decreased glutathione levels in cancer cells exposed to erastin. Further, erastin enhanced the activation of transcription factor 4 (ATF4) in HepG2 and Hep3B cells, and pre‐miR‐214 overexpression inhibited ATF4 expression. The luciferase reporter data validated ATF4 as a direct target of miR‐214. Cancer cells transfected with ATF4 overexpression plasmid rendered lower susceptible to miR‐214‐induced ferroptotic death. In vivo, erastin significantly reduced the size and weight of xenografted tumors, and miR‐214 elevated the ferroptosis‐promoting effects of erastin and decreased ATF4 expression. In summary, our study demonstrates that the ferroptosis‐promoting effects of miR‐214 in hepatoma cells are attributed at least to its inhibitory effects on ATF4, which may provide a new target for therapy of hepatoma regarding ferroptosis.

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“…However, excessive iron can lead to ferroptosis, which has great potential in the treatment of HCC. As a commonly used chemotherapy drug for the treatment of advanced HCC, sorafenib has been found to kill HCC cells by inducing ferroptosis (23). Given the dual role of iron metabolism in HCC, it is valuable to nd new targets in iron metabolism for predicting the prognosis of HCC patients more accurately and providing new treatment strategies.…”

Section: Discussionmentioning

confidence: 99%

Identification of Iron Metabolism-Related Genes Signature and Novel Role of FLVCR1 in Hepatocellular Carcinoma

Chen¹,

Hu²,

Pan³

et al. 2020

Preprint

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Background: Hepatocellular carcinoma (HCC) is the main and highly malignant histological subtype of liver cancer. We tried to construct a novel signature with iron metabolism-related genes to provide new therapeutic targets and improve the prognosis for HCC patients.Methods: The gene expression data of 70 iron metabolism-related genes and its relevant clinical information were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) databases. Consensus clustering analysis was performed to determine clusters of HCC patients with different OS. Cox regression and LASSO regression analyses were used to establish a prognostic signature. Receiver operating characteristic (ROC) and Kaplan–Meier analyses were carried out to examine the predicated performance of the signature.Results: Consensus clustering analysis determined two clusters of HCC patients with different OS(p<0.01), TNM stage(p<0.05) and pathological grade(p<0.05). A nine-gene prognostic signature established with iron metabolism-related genes can independently predicate the prognostic of HCC patients. The ROC curves showed a great performance of the signature. In addition, FLVCR1, a hub gene with the highest mutation frequency in our signature, showed the significantly prognostic value in HCC patients. High FLVCR1 expression was significantly associated with poor prognosis and aggressive progression in HCC patients. The promoter methylation level of FLVCR1 was lower in HCC samples with aggressive progression status. The FLVCR1 expression was positively correlated with the infiltration level of B cell, CD4+ T cell, macrophage, neutrophil and dendritic cell. Conclusion: Our study first established a signature related to iron metabolism and identified FLVCR1 as a potential therapeutic target. These findings provided more treatment strategies for HCC patients.

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Role of ferroptosis in hepatocellular carcinoma

Abstract: In this review, we summarize pathways and mechanisms of ferroptosis in HCC and other digestive system neoplasms such as gastric cancer, pancreatic cancer and colorectal cancer and point out the trends of ferroptosis in HCC.

Cited by 183 publications

References 54 publications

Ferroptosis: past, present and future

Ferroptosis: past, present and future

MicroRNA‐214‐3p enhances erastin‐induced ferroptosis by targeting ATF4 in hepatoma cells

Identification of Iron Metabolism-Related Genes Signature and Novel Role of FLVCR1 in Hepatocellular Carcinoma

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