Downregulation of HuR Inhibits the Progression of Esophageal Cancer through Interleukin-18

Xu, Xiaohui; Song, Cheng; Chen, Zhihua; Yu, Chengbin; Wang, Yi; Tang, Yiting; Luo, Judong

doi:10.4143/crt.2017.013

Cited by 24 publications

(28 citation statements)

References 28 publications

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“…Yu et al [51] recently showed that the RNA-binding protein ELAVL1 promotes bladder cancer progression by competitively binding to the long noncoding HOTAIR with MIR1-1HG. Similarly, Xu et al [52] found that downregulation of ELAVL1 inhibits the progression of esophageal cancer through IL18. Moreover, Badawi et al [53] demonstrated that silencing of the mRNA-binding protein ELAVL1 increases the sensitivity of colorectal cancer cells to ionizing radiation through upregulation of CASP2 (caspase2).…”

Section: Discussionmentioning

confidence: 87%

Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells

et al. 2018

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Ferroptosis is a recently recognized form of regulated cell death that is characterized by lipid peroxidation. However, the molecular mechanisms regulating ferroptosis are largely unknown. In this study, we report that the RNA-binding protein ELAVL1/HuR plays a crucial role in regulating ferroptosis in liver fibrosis. Upon exposure to ferroptosis-inducing compounds, ELAVL1 protein expression was remarkably increased through the inhibition of the ubiquitin-proteasome pathway. ELAVL1 siRNA led to ferroptosis resistance, whereas ELAVL1 plasmid contributed to classical ferroptotic events. Interestingly, upregulated ELAVL1 expression also appeared to increase autophagosome generation and macroautophagic/autophagic flux, which was the underlying mechanism for ELAVL1-enhanced ferroptosis. Autophagy depletion completely impaired ELAVL1-mediated ferroptotic events, whereas autophagy induction showed a synergistic effect with ELAVL1. Importantly, ELAVL1 promoted autophagy activation via binding to the AU-rich elements within the F3 of the 3'-untranslated region of BECN1/Beclin1 mRNA. The internal deletion of the F3 region abrogated the ELAVL1-mediated BECN1 mRNA stability, and, in turn, prevented ELAVL1-enhanced ferroptosis. In mice, treatment with sorafenib alleviated murine liver fibrosis by inducing hepatic stellate cell (HSC) ferroptosis. HSC-specific knockdown of ELAVL1 impaired sorafenib-induced HSC ferroptosis in murine liver fibrosis. Noteworthy, we retrospectively analyzed the effect of sorafenib on HSC ferroptosis in advanced fibrotic patients with hepatocellular carcinoma receiving sorafenib monotherapy. Attractively, ELAVL1 upregulation, ferritinophagy activation, and ferroptosis induction occurred in primary human HSCs from the collected human liver tissue. Overall, these results reveal novel molecular mechanisms and signaling pathways of ferroptosis, and also identify ELAVL1-autophagy-dependent ferroptosis as a potential target for the treatment of liver fibrosis. Abbreviations: ACTA2/alpha-SMA: actin, alpha 2, smooth muscle, aorta; ACTB/beta-actin: actin beta; ARE: AU-rich element; ATG: autophagy related; BDL: bile duct ligation; BECN1: beclin 1; BSO: buthionine sulfoximine; COL1A1: collagen type I alpha 1 chain; ELAVL1/HuR: ELAV like RNA binding protein 1; FDA: fluorescein diacetate; FTH1: ferritin heavy chain 1; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvic transaminase; GPX4: glutathione peroxidase 4; GSH: glutathione; HCC: hepatocellular carcinoma; HSC: hepatic stellate cell; LCM: laser capture microdissection; MAP1LC3B: microtubule associated protein 1 light chain 3 beta; MDA: malondialdehydep; NCOA4: nuclear receptor coactivator 4; PTGS2: prostaglandin-endoperoxide synthase 2; ROS: reactive oxygen species; SQSTM1/p62: sequestosome 1; TBIL: total bilirubin; TEM: transmission electron microscopy; TGFB1: trasforming growth factor beta 1; UTR: untranslated region; VA-Lip-ELAVL1-siRNA: vitamin A-coupled liposomes carrying ELAVL1-siRNA.

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Section: Discussionmentioning

confidence: 87%

Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells

et al. 2018

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“…Recently, a similar study also indicated that HuR protein and mRNA levels were higher in esophageal cancer tissues than in adjacent tissues [62]. The downregulation of HuR significantly inhibited cell proliferation and migration, and the mechanism may be related to the expression of HuR regulating matrix metalloproteinase 2 (MMP2), MMP9, and vimentin [62]. In addition, the overexpression of HuR leads to the increased stability of survivin mRNA and protein expression in esophageal cancer cells, which in turn regulates tumor cell apoptosis and promotes tumor growth [63].…”

Section: Hur and Esophagealmentioning

confidence: 82%

“…Multivariate analysis showed that cytoplasmic HuR expression is an independent prognostic factor for esophageal cancer and that its expression is associated with low survival rates in esophageal cancer [61]. Recently, a similar study also indicated that HuR protein and mRNA levels were higher in esophageal cancer tissues than in adjacent tissues [62]. The downregulation of HuR significantly inhibited cell proliferation and migration, and the mechanism may be related to the expression of HuR regulating matrix metalloproteinase 2 (MMP2), MMP9, and vimentin [62].…”

Section: Hur and Esophagealmentioning

confidence: 90%

The RNA-Binding Protein HuR in Digestive System Tumors

Song

Shi²,

et al. 2020

BioMed Research International

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Human antigen R (HuR) is a member of the Hu family of RNA-binding proteins. This molecule, which was first described in tumors nearly two decades ago, has recently received much attention in tumor-related research because it regulates the expression of many tumor-associated molecules through posttranscriptional regulatory mechanisms, thereby affecting biological characteristics. It is suggested that HuR might be a novel therapeutic target and a marker for therapeutic response and prognostic assessment. Increasing evidence supports that HuR also plays critical roles in the development, therapy, and prognosis of digestive system tumors. Herein, we review the relationships between HuR and digestive system tumors, demonstrating the importance of HuR in digestive system tumor diagnosis.

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“…Downregulation of UQCRC2 in CADH18 overexpressed glioma cell lines, partly reversed the inhibition of invasion/migration ability and chemoresistance . Xu et al . investigated the impact of human antigen R on the progression of esophageal squamous cell carcinoma (ESCC).…”

Section: Discovery Of Potential Drug Targetsmentioning

confidence: 99%

Proteomics in Drug Development: The Dawn of a New Era?

Frantzi

Latosinska

Mischak

2019

Proteomics Clinical Apps

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Mass spectrometry offers the potential of acquiring high resolution data depicting the functional status of a group of healthy or diseased individuals, according to different conditions. As most of the drugs are currently targeting proteins, proteomics has a dual value, both in the discovery of new molecules as therapeutic targets, but also as a methodology to perform high throughput drug profiling. As there is an evident need for drugs to be improved in terms of efficacy, a mechanistic insight for downstream effectors can be valuable in order to predict side effects and resistance mechanisms. Recently developed assays, like thermal proteome profiling enables comprehensive drug target profiling and is, therefore, of high value in drug discovery. In this review, a systematic literature search is conducted and the most prominent proteomics studies as implicated in assisting drug discovery and development is presented. Focus is placed on investigations that are closer to implementation, therefore particular emphasis is given in studies conducted in human diseased population and further verified in vitro or in vivo.

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Downregulation of HuR Inhibits the Progression of Esophageal Cancer through Interleukin-18

Cited by 24 publications

References 28 publications

Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells

Activation of ferritinophagy is required for the RNA-binding protein ELAVL1/HuR to regulate ferroptosis in hepatic stellate cells

The RNA-Binding Protein HuR in Digestive System Tumors

Proteomics in Drug Development: The Dawn of a New Era?

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