Integrated Analysis Reveals Critical Ferroptosis Regulators and FTL Contribute to Cancer Progression in Hepatocellular Carcinoma

Ke, Shao-Ying; Wang, Congren; Su, Zijian; Lin, Shaoze; Wu, Gongle

doi:10.3389/fgene.2022.897683

Cited by 13 publications

(6 citation statements)

References 59 publications

(62 reference statements)

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“…Our three subtypes obtained from unsupervised cluster analysis not only exhibited distinct activities in multiple tumor-related pathways but also had critical significance in scores of FAC. Ke et al (57) indicated that FTL could function as a prognostic and diagnostic ferroptosis regulator in hepatocellular carcinoma via random forest analysis, which was consistent with our results that the FTL-dominant cluster possessed a strong connection with ferroptosis. Their resemble conclusion that higher infiltrating immune cells, including Gamma delta T cells and activated CD8+ T cells, emerged in the high FTL expression group, was also confirmed in our study.…”

Section: Discussionsupporting

confidence: 92%

CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer

Cheng

Liu

et al. 2022

Front. Immunol.

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Currently, breast cancer (BRCA) has become the most common cancer in the world, whose pathological mechanism is complex. Among its subtypes, triple-negative breast cancer (TNBC) has the worst prognosis. With the increasing number of diagnosed TNBC patients, the urgent need of novel biomarkers is also rising. Cyclin-dependent kinase inhibitor 2A (CDKN2A) has recently emerged as a key regulator associated with ferroptosis and cuproptosis (FAC) and has exhibited a significant effect on BRCA, but its detailed mechanism remains elusive. Herein, we conducted the first converge comprehensive landscape analysis of FAC-related gene CDKN2A in BRCA and disclosed its prognostic value in BRCA. Then, an unsupervised cluster analysis based on CDKN2A-correlated genes unveiled three subtypes, namely cold-immune subtype, IFN-γ activated subtype and FTL-dominant subtype. Subsequent analyses depicting hallmarks of tumor microenvironment (TME) among three subtypes suggested strong association between TNBC and CDKN2A. Given the fact that the most clinically heterogeneous TNBC always displayed the most severe outcomes and lacked relevant drug targets, we further explored the potential of immunotherapy for TNBC by interfering CDKN2A and constructed the CDKN2A-derived prognostic model for TNBC patients by Lasso-Cox. The 21-gene–based prognostic model showed high accuracy and was verified in external independent validation cohort. Moreover, we proposed three drugs for TNBC patients based on our model via targeting epidermal growth factor receptor. In summary, our study indicated the potential of CDKN2A as a pioneering prognostic predictor for TNBC and provided a rationale of immunotherapy for TNBC, and offered fresh perspectives and orientations for cancer treatment via inducing ferroptosis and cuproptosis to develop novel anti-cancer treatment strategies.

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Section: Discussionsupporting

confidence: 92%

CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer

Cheng

Liu

et al. 2022

Front. Immunol.

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“…We also evaluated for the expression of key genes and proteins associated with ferroptosis, including TFR1 (responsible for the influx of iron inside the cell), FPN1 (efflux transporter of intracellular iron), FSP1 (ferroptosis suppressor protein 1, inhibits ferroptosis by NAD(P)Hdependent reduction of ubiquinone to ubiquinol), FTH (ferritin heavy chain, converts Fe 2+ to Fe 3+ and stores iron to maintain homeostasis), FTL (ferritin light chain, iron reservoir and removes excess iron), and GPX4 (inhibits lipid peroxidation by converting hydroperoxides into lipid alcohols) and the capacity for molecules with anti-ferroptotic activity to prevent key cellular processes implicated in ferroptosis (36,(52)(53)(54)(55)(56). Results of this investigation provide a basis for future mechanistic investigations of ferroptotic cell death and the prevention of disease progression in FECD.…”

Section: Introductionmentioning

confidence: 99%

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Saha

Skeie

Schmidt

et al. 2022

Preprint

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Fuchs endothelial corneal dystrophy (FECD), a progressive polygenic disease that causes degeneration of the corneal endothelium, is the leading indication for corneal transplantation in the U.S. Characteristically, loss of corneal endothelial cells and formation of degenerative extracellular guttae result in failure to maintain appropriate corneal hydration through active ion pumping to counter the passive leakage of aqueous humor. FECD pathogenesis is linked to oxidative stress and environmental exposure to ultraviolet A (UVA), and impaired endogenous response to oxidative stress is common to the disease across multiple genotypes. UV irradiation is also known to cause cellular damage by ferroptosis, a nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation. Although a possible role for ferroptosis in FECD has been postulated to account for the increased susceptibility to oxidative damage and lipid peroxidation, this has not been explored systematically. In this study, we investigated the roles of genetic background and UVA exposure in causing lipid membrane damage and endothelial cell degeneration in FECD. We first sought clinical evidence of iron-mediated lipid peroxidation in surgical samples obtained from FECD patients undergoing endothelial keratoplasty, and found increased levels of cytosolic ferrous iron (Fe2+) and evidence of lipid peroxidation were present in end-stage diseased tissues compared with healthy human donor corneas. Next, using immortalized (F35T) and primary cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found that alterations in gene and protein expression involved in ferroptosis were conserved in both cell culture and tissue models of FECD disease compared to controls, including elevated levels of the ferroptosis-specific marker transferrin receptor 1. F35T immortalized cells showed significantly higher basal lipid peroxidation than control HCEC-B4G12 cells, indicating higher susceptibility to ferroptosis attributable to genetic background. Then, we tested the impact of physiologically relevant doses of UVA irradiation on F35T cell cultures and found increased cytosolic Fe2+ iron levels indicating a role for ferroptosis in FECD disease progression. Finally, we tested the effects of inhibitory ferroptosis molecules. We found that F35T cells were more prone to RSL3 induced ferroptosis than healthy controls with deferoxamine chelation which indicated increased susceptibility in FECD cells, and cell death could be prevented after experimentally-induced ferroptosis using solubilized antioxidant ubiquinol indicating a role for anti-ferroptosis therapies. This investigation demonstrates that FECD genetic background and UVA exposure contribute to basal and incidental iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated oxidative damage and disease progression in FECD.

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“…SAT1 and SAT2 regulate polyamine metabolism, a process which has long been implicated in cancer [ 73 , 74 ]. Indeed, higher expression of the FTL ferroptosis regulator, is associated with a poorer prognosis in hepatocellular carcinoma [ 75 ]. Further, expression of the voltage-gated channel VDAC2 is also associated with increased risk in some cancers.…”

Section: Resultsmentioning

confidence: 99%

Microbial gene expression analysis of healthy and cancerous esophagus uncovers bacterial biomarkers of clinical outcomes

Schäffer,

Li,

Elbasir

et al. 2023

ISME Communications

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Local microbiome shifts are implicated in the development and progression of gastrointestinal cancers, and in particular, esophageal carcinoma (ESCA), which is among the most aggressive malignancies. Short-read RNA sequencing (RNAseq) is currently the leading technology to study gene expression changes in cancer. However, using RNAseq to study microbial gene expression is challenging. Here, we establish a new tool to efficiently detect viral and bacterial expression in human tissues through RNAseq. This approach employs a neural network to predict reads of likely microbial origin, which are targeted for assembly into longer contigs, improving identification of microbial species and genes. This approach is applied to perform a systematic comparison of bacterial expression in ESCA and healthy esophagi. We uncover bacterial genera that are over or underabundant in ESCA vs healthy esophagi both before and after correction for possible covariates, including patient metadata. However, we find that bacterial taxonomies are not significantly associated with clinical outcomes. Strikingly, in contrast, dozens of microbial proteins were significantly associated with poor patient outcomes and in particular, proteins that perform mitochondrial functions and iron-sulfur coordination. We further demonstrate associations between these microbial proteins and dysregulated host pathways in ESCA patients. Overall, these results suggest possible influences of bacteria on the development of ESCA and uncover new prognostic biomarkers based on microbial genes. In addition, this study provides a framework for the analysis of other human malignancies whose development may be driven by pathogens.

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Integrated Analysis Reveals Critical Ferroptosis Regulators and FTL Contribute to Cancer Progression in Hepatocellular Carcinoma

Cited by 13 publications

References 59 publications

CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer

CDKN2A-mediated molecular subtypes characterize the hallmarks of tumor microenvironment and guide precision medicine in triple-negative breast cancer

TCF4trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy

Microbial gene expression analysis of healthy and cancerous esophagus uncovers bacterial biomarkers of clinical outcomes

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