The essential roles of m6A RNA modification to stimulate ENO1-dependent glycolysis and tumorigenesis in lung adenocarcinoma

Journal of Experimental & Clinical Cancer Research, Год журнала: 2022, Номер 41(1)

Опубликована: Янв. 25, 2022

Lung adenocarcinoma (LUAD) is the most common subtype of lung cancer. Patient prognosis poor, and existing therapeutic strategies for LUAD are far from satisfactory. Recently, targeting N6-methyladenosine (m6A) modification RNA has been suggested as a potential strategy to impede tumor progression. However, roles m6A in tumorigenesis unknown.Global levels expressions writers, erasers readers were evaluated by methylation assay, dot blot, immunoblotting, immunohistochemistry ELISA human LUAD, mouse models cell lines. Cell viability, 3D-spheroid generation, vivo formation, experiments cell- patient-derived xenograft mice survival analysis conducted explore impact on LUAD. The RNA-protein interactions, translation, putative sites glycolysis explored investigation mechanism underlying how stimulates tumorigenesis.The elevation global level specimens resulted combined upregulation writer methyltransferase 3 (METTL3) downregulation eraser alkB homolog 5 (ALKBH5). Elevated was associated with poor overall patients. Reducing knocking out METTL3 overexpressing ALKBH5 suppressed generation cells intra-pulmonary formation mice. Mechanistically, m6A-dependent stimulation occurred via enolase 1 (ENO1). ENO1 mRNA methylated at 359 A, which facilitated it's binding reader YTH protein (YTHDF1) enhanced translation ENO1. positively correlated levels, negatively In addition, preclinical models, tumors higher showed more sensitive response inhibition pan-methylation, ENO activity LUAD.The least partially orchestrated METTL3, ALKBH5, YTHDF1-mediated translation. Blocking this may represent treatment

Язык: Английский

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Homologous targeting nanoparticles for enhanced PDT against osteosarcoma HOS cells and the related molecular mechanisms

Journal of Nanobiotechnology, Год журнала: 2022, Номер 20(1)

Опубликована: Фев. 17, 2022

No prominent advancements in osteosarcoma (OS) treatment have been made the past 20 years. Although photodynamic therapy (PDT) is an emerging technique for cancer therapy, lack of targeted photosensitizers OS severely limits its applications. In this study, we constructed a potential theranostic nanoplatform by using (poly (lactic-co-glycolic) acid (PLGA) nanoparticles (NPs) encapsulating IR780 into shell (PLGA-IR780 NPs), which were further camouflaged with human cell membranes from HOS line (MH-PLGA-IR780 NPs). These NPs showed capacity homologous targeting excellent photoacoustic (PA)/fluorescence (FL) imaging ability. Benefitting their capacity, MH-PLGA-IR780 obviously promoted endocytosis vitro and tumor accumulation vivo, could improve PDT performance under near-infrared (NIR) irradiation. addition, to PA/FL dual-mode ability, had advantages penetrating deeper tissues real-time dynamic distribution monitoring laid foundation clinical applications OS. Moreover, demonstrated that guided significantly induce cells apoptosis ferroptosis via excessive reactive oxygen species (ROS), determined anticancer molecular mechanism was triggered release cytochrome c-activated mitochondrial (endogenous apoptosis), caused activation nuclear receptor coactivator 4 (NCOA4)-mediated ferritinophagy inactivation glutathione peroxidase (GPX4), synergistically leading Lipid-ROS Lipid peroxides (LPOs). Concurrently, NPs-guided also obvious inhibitory effect on growth vivo. results suggest targeting-based provides effective method contributes new promising approach therapy.

Язык: Английский

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m6A methylation: a process reshaping the tumour immune microenvironment and regulating immune evasion

Molecular Cancer, Год журнала: 2023, Номер 22(1)

Опубликована: Март 1, 2023

Abstract N6-methyladenosine (m 6 A) methylation is the most universal internal modification in eukaryotic mRNA. With elaborate functions executed by m A writers, erasers, and readers, modulation involved myriad physiological pathological processes. Extensive studies have demonstrated diverse tumours, with effects on tumorigenesis, metastasis, resistance. Recent evidence has revealed an emerging role of tumour immunoregulation, divergent patterns been microenvironment. To depict regulatory immune microenvironment (TIME) its effect evasion, this review focuses TIME, which characterized hypoxia, metabolic reprogramming, acidity, immunosuppression, outlines A-regulated TIME evasion under stimuli. Furthermore, anti-tumour cells are summarized.

Язык: Английский

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Ferroptosis in lung cancer: a novel pathway regulating cell death and a promising target for drug therapy

Cell Death Discovery, Год журнала: 2023, Номер 9(1)

Опубликована: Апрель 1, 2023

Lung cancer is a common malignant tumor that occurs in the human body and poses serious threat to health quality of life. The existing treatment methods mainly include surgical treatment, chemotherapy, radiotherapy. However, due strong metastatic characteristics lung emergence related drug resistance radiation resistance, overall survival rate patients not ideal. There an urgent need develop new strategies or effective drugs treat cancer. Ferroptosis, novel type programmed cell death, different from traditional death pathways such as apoptosis, necrosis, pyroptosis so on. It caused by increase iron-dependent reactive oxygen species intracellular iron overload, which leads accumulation lipid peroxides, thus inducing membrane oxidative damage, affecting normal life process cells, finally promoting ferroptosis. regulation ferroptosis closely physiological it involves metabolism, balance between oxygen-free radical reaction peroxidation. A large number studies have confirmed result combined action cellular oxidation/antioxidant system damage/repair, has great potential application therapy. Therefore, this review aims explore therapeutic targets for clarifying regulatory pathway Based on study ferroptosis, mechanism was understood chemical natural compounds targeting were summarized, with aim providing ideas In addition, also provides basis discovery clinical effectively

Язык: Английский

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Exploring Cr(VI)-induced blood-brain barrier injury and neurotoxicity in zebrafish and snakehead fish, and inhibiting toxic effects of astaxanthin

Environmental Pollution, Год журнала: 2024, Номер 355, С. 124280 - 124280

Опубликована: Май 28, 2024

Язык: Английский

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METTL3 promotes colorectal carcinoma progression by regulating the m6A–CRB3–Hippo axis

Journal of Experimental & Clinical Cancer Research, Год журнала: 2022, Номер 41(1)

Опубликована: Янв. 10, 2022

Colorectal carcinoma (CRC) is the third most common cancer and second cause of cancer-related deaths worldwide. Ribonucleic acid (RNA) N6-methyladnosine (m6A) methyltransferase-like 3 (METTL3) play key roles in progression. However, m6A METTL3 CRC progression require further clarification.Adenoma samples were examined to detect levels, tissue microarrays performed evaluate association levels with survival patients CRC. The biological functions investigated through cell counting kit-8, wound healing, transwell assays. M6A epitranscriptomic microarray, methylated RNA immunoprecipitation-qPCR, stability, luciferase reporter, immunoprecipitation assays explore mechanism progression.M6A substantially elevated tissues, a high or exhibited shorter overall survival. knockdown inhibited proliferation, migration, invasion cells. An microarray revealed that polarity regulator Crumbs3 (CRB3) was downstream target METTL3. reduced level CRB3, degradation CRB3 mRNA increase expression. Luciferase reporter also showed transcriptional wild-type significantly increased after but not its variation. Knockdown YT521-B homology domain-containing family protein 2 (YTHDF2) verified direct interaction between YTHDF2 mRNA, this impaired inhibition. In addition, promoted Mechanistically, activated Hippo pathway nuclear localization Yes1-associated regulator, effects reversed by knockdown.M6A tissues relative normal tissues. Patients survival, regulated regulating m6A-CRB3-Hippo pathway.

Язык: Английский

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Insight into the structure, physiological function, and role in cancer of m6A readers—YTH domain-containing proteins

Cell Death Discovery, Год журнала: 2022, Номер 8(1)

Опубликована: Март 28, 2022

Abstract YT521-B homology (YTH) domain-containing proteins (YTHDF1-3, YTHDC1-2) are the most crucial part of N6-methyladenosine (m6A) readers and play a regulatory role in almost all stages methylated RNA metabolism progression various cancers. Since m6A is identified as an essential post-transcriptional type, YTH have played key sites RNA. Hence, it great significance to study interaction between family m6A-modified tumor. In this review, their basic structure physical functions transcription, splicing, exporting, stability, degradation well protein translation introduced. Then we discussed expression regulation Furthermore, introduced cancer biology systematically demonstrated aspects tumorigenesis development. To provide more institute understanding cancers, summarized specific mechanisms types presented involvement cancer-related signaling pathways.

Язык: Английский

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IGF2BP3 is an essential N6-methyladenosine biotarget for suppressing ferroptosis in lung adenocarcinoma cells

Materials Today Bio, Год журнала: 2022, Номер 17, С. 100503 - 100503

Опубликована: Ноя. 24, 2022

A lack of promising targets leads to poor prognosis in patients with lung adenocarcinoma (LUAD). Therefore, it is urgent identify novel therapeutic targets. The importance the N6-methyladenosine (m6A) RNA modification has been demonstrated various types tumors; however, knowledge m6A-related proteins LUAD still limited. Here, we found that insulin-like growth factor 2 mRNA binding protein 3 (IGF2BP3), an m6A reader protein, highly expressed and associated prognosis. IGF2BP3 desensitizes ferroptosis (a new form regulated cell death) a manner dependent on its reading domain capacity m6A-methylated mRNAs encoding anti-ferroptotic factors, including but not limited glutathione peroxidase 4 (GPX4), solute carrier family member (SLC3A2), acyl-CoA synthetase long chain (ACSL3), ferritin heavy 1 (FTH1). After overexpression, expression levels stabilities these factors were successfully sustained. Notably, significant correlations between SLC3A2, ACSL3, revealed clinical specimens, further establishing essential role desensitizing ferroptosis. Inducing gradually accepted as alternative strategy treat tumors. Thus, could be potential target for future development biomaterial-associated anti-tumor drugs.

Язык: Английский

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Exosomal miR-142-3p secreted by hepatitis B virus (HBV)-hepatocellular carcinoma (HCC) cells promotes ferroptosis of M1-type macrophages through SLC3A2 and the mechanism of HCC progression

Journal of Gastrointestinal Oncology, Год журнала: 2022, Номер 13(2), С. 754 - 767

Опубликована: Апрель 1, 2022

Background: Most patients with hepatitis B virus (HBV) infection will develop hepatocellular carcinoma (HCC). This study aimed to explore the potential mechanism of miR-142-3p in HCC caused by HBV infection. Methods: HepG2 cells and M1 macrophages were cocultured then infected establish an vitro model. MicroRNA (miRNA) messenger RNA (mRNA) expression was analyzed quantitative reverse transcription polymerase chain reaction (RT-qPCR) Western blot. The protein expressions COX2, ACSL4, PTGS2, GPX4, NOX1 Flow cytometry TUNEL assays used assess cell reactive oxygen species (ROS) ferroptosis, respectively. Cell invasion migration measured Transwell assay. To evaluate ferroptosis M1-type macrophages, glutathione (GSH), malondialdehyde (MDA), Fe2+ content detected corresponding kits. Dual luciferase reporter gene detection verified targeting relationship between SLC3A2. Results: MiR-142-3p highly expressed HBV-infected macrophages. Inhibition or overexpression SLC3A2 reversed inhibited proliferation, migration, cells. Conclusions: Our findings indicated that promoted macrophage through SLC3A2, affecting production GSH, MDA, accelerating development HCC. regulation its target genes help clarify pathogenesis induced provide new theoretical foundations therapeutic targets.

Язык: Английский

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Multifaceted Roles of Ferroptosis in Lung Diseases

Frontiers in Molecular Biosciences, Год журнала: 2022, Номер 9

Опубликована: Июнь 24, 2022

Ferroptosis is a distinct type of programmed cell death (PCD) that depends on iron and characterized by the accumulation intracellular iron, exhaustion glutathione, deactivation glutathione peroxidase, promotion lipid peroxidation. Recently, accumulated investigations have demonstrated ferroptosis strongly correlated with initiation development many lung diseases. In this review, we summarized contribution to pathologic process diseases, namely, obstructive diseases (chronic pulmonary disease, asthma, cystic fibrosis), interstitial (pulmonary fibrosis different causes), vascular origin (ischemia-reperfusion injury hypertension), infections (bacteria, viruses, fungi), acute injury, respiratory distress syndrome, sleep apnea, alveolar proteinosis, cancer. We also discussed therapeutic potential targeting for these

Язык: Английский

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