ACSL4 promotes hepatocellular carcinoma progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis

Chen, Junru; Ding, Chaofeng; Chen, Yunhao; Hu, Wendi; Lu, Yuejie; Wu, Wenxuan; Zhang, Yanpeng; Yang, Beng; Wu, Hao; Peng, Chuanhui; Xie, Haiyang; Zhou, Lin; Wu, Jian; Zheng, Shusen

doi:10.1038/s41389-020-0226-z

Cited by 68 publications

(67 citation statements)

References 38 publications

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“…The absence of NFAT2 in carcinoma tissues would enhance the activation of AKT and ERK. The activated ERK could phosphorylate Ser62 site in c-myc and thus stabilize the c-myc [28], while the activation of AKT promoted COX-2 expression and COX-2 dependent pro-metastasis [29]. In the current study, the expression of c-myc and COX-2 was obviously increased in carcinoma tissues, which was in agree with the previous research and our deduction.…”

Section: Discussionsupporting

confidence: 92%

NFAT2 overexpression suppresses the malignancy of hepatocellular carcinoma through inducing Egr2 expression

Wang

Zhang

Liu

et al. 2020

Preprint

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PURPOSE Nuclear factor of activated T cells 2 (NFAT2) has been reported to regulate the development and malignancy of few tumors. In this study, we aimed to explore the effect of NFAT2 expression on cell fate of HepG2 cell and its potential mechanisms. METHODS Firstly, the pcDNA3.1-NFAT2 plasmid was transfected into HepG2 cells to construct NFAT2 overexpressed HepG2 cells. Then, the chemical count kit-8 cell viability assay, Annexin V-FITC apoptosis detection, EdU labeling proliferation detection, transwell and wound healing experiments were performed. The expression of Egr2 and FasL, and the phosphorylation of AKT and ERK, after ionomycin and PMA co-stimulation, were detected, while the Ca2+ mobilization stimulated by K+ solution were determined. At last, the mRNA and protein expression of NFAT2, Egr2, FasL, COX-2 and c-myc in carcinoma and adjacent tissues was investigated. RESULTS The NFAT2 overexpression suppressed the cell viability, invasion and migration, and promoted apoptosis of HepG2 cells. NFAT2 overexpression induced the expression of Egr2 and FasL, and suppressed the phosphorylation of AKT and ERK. The sensitivity and Ca2+ mobilization of HepG2 cells was also inhibited by NFAT2 overexpression. Compared with adjacent tissues, the carcinoma tissues expressed less NFAT2, Egr2, FasL and more COX-2 and c-myc. CONCLUSION The current study firstly demonstrated that NFAT2 suppressed the aggression and malignancy of HepG2 cells through inducing the expression of Egr2. The absence of NFAT2 and Egr2 in carcinoma tissues reminded us that NFAT2 may be a promising therapeutic target for hepatocellular carcinoma treatment.

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Section: Discussionsupporting

confidence: 92%

NFAT2 overexpression suppresses the malignancy of hepatocellular carcinoma through inducing Egr2 expression

Wang

Zhang

Liu

et al. 2020

Preprint

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“…Interestingly, ACSL4 and ALOX5 were found to be significantly up-regulated in HCC patients with high CIFI values, even though they facilitate the execution of ferroptosis ( Liu et al, 2015 ; Yuan et al, 2016 ; Doll et al, 2017 ). However, it is worth noting that both ACSL4 and ALOX5 are over-expressed in HCC as compared to normal livers, and promote the progression of the disease ( Xu et al, 2011 ; Chen et al, 2020 ; Ndiaye et al, 2020 ; Wang et al, 2020 ). Thus, the over-expression of ACSL4 and ALOX5 contributes to the proliferation and progression of HCC, but renders the patients more susceptible to ferroptosis inducers.…”

Section: Discussionmentioning

confidence: 99%

Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma

Liu

Zhang

et al. 2020

Front. Cell Dev. Biol.

102

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BackgroundImmunotherapy and sorafenib exert anti-tumor effects via ferroptosis, but reliable biomarkers for the individual treatment and prognosis prediction of hepatocellular carcinoma (HCC) based on the ferroptosis and immune status remain lacking.MethodsFerroptosis-related genes (FRGs) were identified by downloading data from FerrDb and by searching and reading original articles from PubMed. Immune-related genes (IRGs) were downloaded from ImmPort. Prognostic FRGs and IRGs in the GSE14520 (n = 220) and The Cancer Genome Atlas (TCGA, n = 365) datasets were identified. Least absolute shrinkage and selection operator (LASSO) Cox regression and multivariate Cox regression were used for model construction. Ferroptosis expression profiles, the infiltration of immune cells, and the somatic mutation status were analyzed and compared.ResultsTwenty-seven prognostic ferroptosis- and immune-related signatures were included to construct a comprehensive index of ferroptosis and immune status (CIFI). A subgroup of patients was identified as having a high CIFI value, which was associated with a worse prognosis. This subgroup of patients had significantly up-regulated expressions of many suppressors of ferroptosis and higher fractions of immunosuppressive cells, such as cancer-associated fibroblasts (CAFs) and myeloid-derived suppressor cells (MDSCs). Notably, somatic mutation analysis indicated that high-CIFI patients had higher levels of tumor heterogeneity and higher mutation frequencies of genes like TP53.ConclusionIn this work, a novel prognostic classifier was developed based on ferroptosis- and IRGs in HCC, and this classifier could be used for prognostic prediction and the selection of patients for immunotherapies and targeted therapies.

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“…In addition to regulating the synthesis and degradation of lipids, ACSL4 has been found overexpressed in several origins of cancer [50][51][52]. It is noteworthy that ACSL4 favors tumor progression in HCC via stabilization of the oncoprotein c-myc through the ubiquitin-proteasome system [53], and the mRNA expression of ACSL4 in HepG2 cells was substantially higher than that in Hep3B cells [53] which is in accordance with the gene expression pattern obtained from the Cancer Cell Line Encyclopedia database (data not shown). Therefore, the higher sensitivity of HepG2 cells to FC-induced ferroptosis may be, at least in part, attributed to the higher expression of ACSL4.…”

Section: Discussionmentioning

confidence: 99%

Saponin Formosanin C-Induced Ferritinophagy and Ferroptosis in Human Hepatocellular Carcinoma Cells

Lin

Tang

et al. 2020

Antioxidants

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Ferroptosis, a recently discovered form of iron-dependent cell death, requires an increased level of lipid-reactive oxygen species (ROS). Ferritinophagy, a ferritin degradation pathway, depends on a selective autophagic cargo receptor (NCOA4). By screening various types of natural compounds, formosanin C (FC) was identified as a novel ferroptosis inducer, characterized by attenuations of FC-induced viability inhibition and lipid ROS formation in the presence of ferroptosis inhibitor. FC also induced autophagic flux, evidenced by preventing autophagic marker LC3-II degradation and increasing yellow LC3 puncta in tandem fluorescent-tagged LC3 (mRFP-GFP) reporter plasmid (ptfLC3) transfected cells when combined with autophagic flux inhibitor. It is noteworthy that FC-induced ferroptosis and autophagic flux were stronger in HepG2 cells expressing higher NCOA4 and lower ferritin heavy chain 1 (FTH1) levels, agreeing with the results of gene expression analysis using CTRP and PRISM, indicating that FTH1 expression level exhibited a significant negative correlation with the sensitivity of the cells to a ferroptosis inducer. Confocal and electron microscopy confirmed the pronounced involvement of ferritinophagy in FC-induced ferroptosis in the cells with elevated NCOA4. Since ferroptosis is a non-apoptotic form of cell death, our data suggest FC has chemotherapeutic potential against apoptosis-resistant HCC with a higher NCOA4 expression via ferritinophagy.

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ACSL4 promotes hepatocellular carcinoma progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis

Cited by 68 publications

References 38 publications

NFAT2 overexpression suppresses the malignancy of hepatocellular carcinoma through inducing Egr2 expression

NFAT2 overexpression suppresses the malignancy of hepatocellular carcinoma through inducing Egr2 expression

Development and Validation of a Combined Ferroptosis and Immune Prognostic Classifier for Hepatocellular Carcinoma

Saponin Formosanin C-Induced Ferritinophagy and Ferroptosis in Human Hepatocellular Carcinoma Cells

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