Ferroptosis-related genes with post-transcriptional regulation mechanisms in hepatocellular carcinoma determined by bioinformatics and experimental validation

Zhu, Renfei; Cheng, Gao; Feng, Qiuqi; Guan, Huaijin; Wu, Jianjun; Samant, Hrishikesh; Yang, Fan; Wang, Xuehao

doi:10.21037/atm-22-5750

Cited by 10 publications

(4 citation statements)

References 59 publications

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“…We searched 177 articles focused on m6A and HCC, and about 35 works of literature have studied the expression characteristics, clinical prognosis, immune microenvironment, and immunotherapy of m6A in HCC through bioinformatics analysis (29,34). Some articles have further used cell lines to verify their analysis in vitro (35,36). Studies based on in vitro and in vivo experiments primarily involve patient samples and HCC cell lines (37)(38)(39).…”

Section: Discussionmentioning

confidence: 99%

Identification of METTL3 as a myeloid-related prognosis biomarker in hepatocellular carcinoma using bioinformatics analysis and engineered mice model

Wang

Yang

et al. 2023

Preprint

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Background Hepatocellular carcinoma (HCC) is a significant contributor to cancer-related mortality, ranking third in this regard. The epigenetic regulation of RNA N6-methyladenosine (m6A) modification in HCC has garnered considerable attention. This study utilized bioinformatics analysis and biologically engineered mice models to explore the immune and prognostic role of m6A modification in HCC. Methods We systematically analyzed genetic alterations, expression patterns, signaling pathways, prognostic features, and immunotherapy efficacy of the 21 m6A regulators in HCC as obtained from the Cancer Genome Atlas (TCGA), the Gene Expression Omnibus (GEO, GSE14520, GSE76427), and International Cancer Genome Consortium (IGCG) database; Unsupervised clustering, gene set variation analysis (GSVA), LASSO-COX regression, multivariate Cox regression, Nomogram, receiver operating characteristic (ROC) analysis, TIMER 2.0 and ImmuCellAI were used to perform the above analysis. Our analysis was verified with Mettl3F/FAlbumin-cre (liver-specific knockout, LKO) mice to establish a chemo-induced HCC model. The tumor immune microenvironment was analyzed with immunohistochemistry, immunofluorescence staining, and flow cytometry. Results The genetic alteration of the m6A modification gene set exhibited a correlation with reduced progression-free survival, diminished abundance of macrophage cells, and a lower score for immune cell infiltration. The cluster characterized by lower expression of the m6A gene set was linked to a more favorable overall survival (OS) and immune signaling, including IL2-STAT5, IL6-STAT3, IFN-gamma, and IFN-alpha signaling. Notably, the cluster with higher expression of m6A was associated with a higher homologous recombination deficiency (HRD) score and tumor mutational burden (TMB) score. Results of LASSO COX and the nomogram model underscored the significant contribution of METTL3 in the prognosis and ICB therapy of HCC. The results of Mettl3 LKO mice confirmed that Mettl3 LKO acted as a "rheostat" in the progression of HCC by regulating the mouse liver's myeloid-related innate and adaptive immune landscape. Conclusions In this study, we characterized the genetic, immune, and clinic landscape of the m6A gene set in HCC development and unveiled METTL3 as a molecular biomarker in epigenetic-related progress and ICB therapy of HCC from both informatics database analysis and engineered mice model.

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Section: Discussionmentioning

confidence: 99%

Identification of METTL3 as a myeloid-related prognosis biomarker in hepatocellular carcinoma using bioinformatics analysis and engineered mice model

Wang

Yang

et al. 2023

Preprint

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“…hances its mRNA stability in a YTHDF1-dependent manner, with YTHDF1 inhibiting ferroptosis by upregulating FTH in lung cancer [74][75][76][77]. Other RNA methylation modifications, such as m1A and m5C, have also been reported to be involved in the post-transcriptional modification of ferroptosis-related genes [78,79]. Therefore, more RNA methylation targets that regulate ferroptosis need to be discovered in further studies to provide insights for clinical treatment (Figure 2).…”

Section: Rna Methylation Regulates Ferroptosismentioning

confidence: 99%

Insights into the Roles of Epigenetic Modifications in Ferroptosis

Kong,

Lyu,

Ouyang

et al. 2024

Biology

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Ferroptosis is a non-apoptotic mode of cell death driven by membrane lipid peroxidation and is characterized by elevated intracellular levels of Fe2+, ROS, and lipid peroxidation. Studies have shown that ferroptosis is related to the development of multiple diseases, such as cancer, neurodegenerative diseases, and acute myeloid leukemia. Ferroptosis plays a dual role in the occurrence and development of these diseases. Ferroptosis mainly involves iron metabolism, ROS, and lipid metabolism. Various mechanisms, including epigenetic regulation, have been reported to be deeply involved in ferroptosis. Abnormal epigenetic modifications have been reported to promote tumor onset or other diseases and resistance to chemotherapy drugs. In recent years, diversified studies have shown that epigenetic modification is involved in ferroptosis. In this review, we reviewed the current resistance system of ferroptosis and the research progress of epigenetic modification, such as DNA methylation, RNA methylation, non-coding RNAs, and histone modification in cancer and other diseases by regulating ferroptosis.

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“…In the past three years, several studies have shown that RNA m 6 A marks are involved in the regulation of ferroptosis and thus affects the progression of diseases such as tumor growth and acute kidney injury [133,150,151] and that m 6 A modification regulators used in combination with ferroptosis-related genes can be diagnostic or prognostic markers for tumors in humans [130,[152][153][154][155]. Multiple m 6 A modification regulators have been shown to be aberrantly expressed in various types of tumors, and a prediction model comprising these regulators and ferroptosis-associated genes has been shown to effectively reflect the progression and prognosis of these tumor patients [23,[156][157][158][159]. Recently, our research revealed that compared to aortic samples without aortic dissection (non-AD), higher levels of METTL3 and METTL14 protein, but lower levels of FTO were detected in aortic samples with Stanford type A aortic dissection (TAAD) [3].…”

Section: The Rna M 6 a Modification In Ferroptosismentioning

confidence: 99%

“…Multiple m 6 A modification regulators have been shown to be aberrantly expressed in various types of tumors, and a prediction model comprising these regulators and ferroptosis-associated genes has been shown to effectively reflect the progression and prognosis of these tumor patients 23 , 156 - 159 . Recently, our research revealed that compared to aortic samples without aortic dissection (non-AD), higher levels of METTL3 and METTL14 protein, but lower levels of FTO were detected in aortic samples with Stanford type A aortic dissection (TAAD) 3 .…”

Section: The Rna M 6 a Modification In Ferroptosismentioning

confidence: 99%

Effects of DNA, RNA, and Protein Methylation on the Regulation of Ferroptosis

Wang¹,

Kong²,

Feng³

et al. 2023

Int. J. Biol. Sci.

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Ferroptosis is a form of programmed cell death characterized by elevated intracellular ferrous ion levels and increased lipid peroxidation. Since its discovery and characterization in 2012, considerable progress has been made in understanding the regulatory mechanisms and pathophysiological functions of ferroptosis. Recent findings suggest that numerous organ injuries (e.g., ischemia/reperfusion injury) and degenerative pathologies (e.g., aortic dissection and neurodegenerative disease) are driven by ferroptosis. Conversely, insufficient ferroptosis has been linked to tumorigenesis. Furthermore, a recent study revealed the effect of ferroptosis on hematopoietic stem cells under physiological conditions. The regulatory mechanisms of ferroptosis identified to date include mainly iron metabolism, such as iron transport and ferritinophagy, and redox systems, such as glutathione peroxidase 4 (GPX4)-glutathione (GSH), ferroptosis-suppressor-protein 1 (FSP1)-CoQ10, FSP1-vitamin K (VK), dihydroorotate dehydrogenase (DHODH)-CoQ, and GTP cyclohydrolase 1 (GCH1)-tetrahydrobiopterin (BH4). Recently, an increasing number of studies have demonstrated the important regulatory role played by epigenetic mechanisms, especially DNA, RNA, and protein methylation, in ferroptosis. In this review, we provide a critical analysis of the molecular mechanisms and regulatory networks of ferroptosis identified to date, with a focus on the regulatory role of DNA, RNA, and protein methylation. Furthermore, we discuss some debated findings and unanswered questions that should be the foci of future research in this field.

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Ferroptosis-related genes with post-transcriptional regulation mechanisms in hepatocellular carcinoma determined by bioinformatics and experimental validation

Cited by 10 publications

References 59 publications

Identification of METTL3 as a myeloid-related prognosis biomarker in hepatocellular carcinoma using bioinformatics analysis and engineered mice model

Identification of METTL3 as a myeloid-related prognosis biomarker in hepatocellular carcinoma using bioinformatics analysis and engineered mice model

Insights into the Roles of Epigenetic Modifications in Ferroptosis

Effects of DNA, RNA, and Protein Methylation on the Regulation of Ferroptosis

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