BRITISH JOURNAL OF PHARMACOLOGY
·
2026
·
IF 7.5
Yufen Xu,Xiaoli Tan,Xiaodong Lv,Qi Yang,Xingxing Ke,Wenyu Chen
Background and Purpose IGF2BP1 stabilizes oncogenic mRNAs via m6A binding to drive lung adenocarcinoma (LUAD) progression, yet how this modification orchestrates immune evasion remains unclear. Experimental Approach Bioinformatics, RT-qPCR and Western Blotting (WB) first profiled IGF2BP1 expression in LUAD. RNA pull-down, IL-11 stability assays, ELISA and confocal imaging screened and validated IGF2BP1/IL-11 as the key oncogenic axis. ELISA, cytotoxicity experiments and flow cytometry were applied in the exploration of the function of the IGF2BP1/IL-11 axis in LUAD. Bioinformatics analysis, IGF2BP1 half-life detection, WB and ubiquitination experiments were employed to identify the interaction between KCTD10 and IGF2BP1. Allograft experiments were conducted to validate the impact of the KCTD10/IGF2BP1/IL-11 axis on tumour immune escape. Clinical correlation analysis was based on samples of LUAD patients before and after PD-1/PD-L1 inhibitor treatment. Key Results IGF2BP1 was up-regulated in LUAD, exhibiting an association with adverse prognosis. Mechanistically, we observed that IGF2BP1 stabilized IL-11 mRNA in an N6-methyladenosine (m6A)-dependent manner, leading to higher protein expression of IL-11, thereby dampening the cytotoxicity and proliferation of CD8 + cells as well as the expression of TNF-α, IFN-γ and IL-2. Furthermore, KCTD10 overexpression facilitated ubiquitination and degradation of IGF2BP1, and its combination with an anti-IL-11 monoclonal antibody dramatically enhanced therapeutic efficacy. Conclusion and Implications These findings reveal that KCTD10 degrades IGF2BP1 by ubiquitination, regulates m6A modification of IL-11, and restrains immune evasion in LUAD. Our study identifies potential targets for immunotherapy and proffers new therapeutic options for LUAD patients.
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SENSORS AND ACTUATORS B-CHEMICAL
·
2023
·
IF 8.4
Xixiang Xie,Xiyu Liu,Wenxi Lu,Tao Wu,Jian He,Zhiming Deng,Faquan Lin,Pan Wu,Bing Wang,Yong Huang
N 6 -methyladenosine (m 6 A) modification has an impact on RNA metabolism, and it has been demonstrated that m 6 A regulatory mechanisms play an important role in tumorigenesis and may serve as a potential hepatocellular carcinoma (HCC) marker. We constructed a dual-signal amplification strategy electrochemical biosensor based on biocatalytic silver deposition and hybridization chain reaction (HCR). Enzymatic silver deposition was performed on the electrode and detected by linear sweep voltammetry (LSV), which was used for the quantitative detection of m 6 A. There was a nice linear relationship between the current response values and the logarithm of the m 6 A RNA concentration in the range of 0.5 pM-5 μM, with a detection limit as low as 25 fM. The concentration of m 6 A detected by the sensor constructed in this work is consistent with the results obtained using commercial colorimetric immunoassays . What's more, the analysis of m 6 A RNA in the serum of HCC patients using the developed sensor showed the high analytical efficiency of the designed strategy, which was superior to three other markers (AFP, CEA, CA199). The constructed electrochemical biosensor has good sensitivity, specificity and reproducibility for the detection of m 6 A RNA, and the sensing platform has promising clinical applications in the diagnosis and prognosis of HCC.
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ANALYTICA CHIMICA ACTA
·
2023
·
IF 6.2
Huahui Gao,Xinmei Song,Qirong Chen,Ruo Yuan,Yun Xiang
The demethylase of fat mass and obesity related protein (FTO) is critical to regulate the dynamic N 6 -methyladenosine (m6A) modification of eukaryotic mRNAs, and its overexpression has found to be closely related to the initiation of several cancers. On the basis of a target-promoted specific activation of DNAzyme strategy coupled with self-primer exponential amplification reaction (SPEXPAR) cycles and DNA supersandwich assemblies, the highly sensitive and label-free electrochemical FTO assay approach is established. The modification of the catalytic core nucleobase of the DNAzyme probe by m6A can inhibit its cleavage activity. The presence of target FTO catalyzes the elimination of the methyl group to restore the DNAzyme activity, which cleaves the hairpin substrates to trigger the SPEXPAR for yielding many ssDNAs. The capture of these DNAs on the sensor electrode leads to the initiation of supersandwich assembly formation of long dsDNAs . Tremendous electrochemical signal probe of [Ru(NH 3 ) 6 ]Cl 3 are then absorbed on these dsDNAs to produce highly amplified catalytic currents with the assistance of K 3 [Fe(CN) 6 ] for detecting trace FTO with 63.1 fM detection limit. Furthermore, the sensor can be employed for selective assay of FTO in cell lysates, revealing the great potential of this sensing strategy for biomedical and biological study applications.
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SCIENCE OF THE TOTAL ENVIRONMENT
·
2021
·
IF 7.963
Limei Sun,Ming Gao,Qiuhui Qian,Ziyi Guo,Peng Zhu,Xuedong Wang,Huili Wang
Chronic exposure of triclosan (TCS) to zebrafish triggers high incidence of fatty liver and hepatitis; however, the underlying molecular mechanisms remain unclear. Herein, we identified miR-30b as a sensitive biomarker to TCS stress, reflecting in that its decreased expression caused metabolic toxicity, abnormal development and behavior, and lipid-metabolism disorder. By microinjecting the inhibitor and mimic experiments, miR-30b was proved to regulate lipid metabolism by its main target gene fto . Over-expression of FTO resulted in fat accumulation, elevation of the TG and TC levels and up-regulation of the PPARγ and CEBPα, as well as decrease of the global m 6 A level in larvae. On the contrary, the knock-down of FTO using MO caused the anti-lipogenic effect, decrease of the TG and T-CHO levels, and abnormal changes of cebpɑ , acsl 5, fasn , ppap 2c and ppar γ etc. Further fortification tests of cycloleucine and betaine evidenced that the toxic effect was strongly dependent on regulation of the m 6 A level. The toxicity effects in the treatments of methylated donors and receptors were consistent with the changes in physiological functions of FTO knockdown and overexpression. The effects of cycloleucine on m 6 A level and lipid metabolism generally consisted with those of FTO, but this was not the case for betaine, reflecting in increased m 6 A level and lipid accumulation in larval liver. Consequently, we posit that TCS exposure caused zebrafish lipid-metabolism disorder by decreasing miR-30b expression to regulate fto-mediated m 6 A methylation level. These findings contribute to our deep understanding of the underlying molecular mechanisms regarding contaminant-originating fatty liver and hepatocellular carcinoma, and also have practical significance in pollution warning and target therapy for related diseases.
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LABORATORY INVESTIGATION
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2024
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IF 5.1
Rui Hou,Yadong Wang,Shiyao Cao,Xinrui Sun,Luo Jiang
High-grade serous ovarian cancer (HGSOC) remains the most lethal female cancer by far. Herein, clinical HGSOC samples had higher N 6 -methyladenosine (m 6 A) modification than normal ovarian tissue, and its dysregulation had been reported to drive aberrant transcription and translation programs. However, Kringle containing transmembrane protein 2 (KREMEN2) and its m 6 A modification have not been fully elucidated in HGSOC. In this study, the data from the high-throughput mRNA sequencing (RNA-seq) of clinical samples were processed using the weighted correlation network analysis (WGCNA) and functional enrichment analysis. Results revealed that KREMEN2 was a driver gene in the tumorigenesis of HGSOC and a potential target of m 6 A demethylase fat-mass and obesity-associated protein (FTO). KREMEN2 and FTO levels were upregulated and downregulated, respectively, and correlation analysis showed a significant negative correlation in HGSOC samples. Importantly, upregulated KREMEN2 was remarkably associated with lymph node (LN) metastasis, distant metastasis, peritoneal metastasis, and high FIGO stage (Ⅲ/Ⅳ), independent of the age of patients. KREMEN2 promoted the growth of HGSOC in vitro and in vivo , which was dependent on FTO. The methylated RNA immunoprecipitation-qPCR and RNA immunoprecipitation assays were performed to verify the m 6 A level and sites of KREMEN2. FTO overexpression significantly decreased m 6 A modification in 3'UTR and 5'UTR regions of KREMEN2 mRNA and downregulated its expression. In addition, we found that FTO-mediated m 6 A modification of KREMEN2 mRNA was recognized and stabilized by the m 6 A reader IGF2BP1 rather than IGF2BP2 or IGF2BP3. This study highlights the m 6 A modification of KREMEN2 and extends the importance of RNA epigenetics in HGSOC.
研究领域:
癌症生物学
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分子生物学
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表观遗传学
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肿瘤学
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ACS Applied Materials & Interfaces
·
2023
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IF 9.5
Zhiyong Guo,Zilin Wang,Yige Liu,Hao Wu,Qiaoyu Zhang,Jing Han,Jiannan Liu,Chenping Zhang
Radiation-induced bone injury management remains a challenge in clinical practice, and there is no effective medicine. Recently, biomass-derived carbon dots (CDs) have attracted attention in biomedical engineering due to the advantages of abundant heteroatoms, low toxicity, and no need to drug loading. Here, we report that CDs, synthesized from Lycium barbarum via hydrothermal strategy, can effectively alleviate radiation-induced bone injury. CCK-8, apoptosis analysis, β-galactosidase staining, quantitative polymerase chain reaction, and western blots demonstrate that CDs can mediate radiation-induced damage and senescence of bone marrow mesenchymal stem cells (BMSCs). CDs regulate osteogenic- and adipogenic-balance after irradiation, shown by alizarin red and oil red O staining. In vivo experiments reveal that CDs prevent the occurrence of osteoradionecrosis in rats, demonstrated by micro-CT and histology examination. The osseointegration of titanium implants installed in irradiated bone is promoted by CDs. Mechanistically, CDs increase the N6-methyladenosine (m6A) level of irradiated BMSCs via the increased methyltransferase-like 3 (METTL3). High-throughput sequencing facilitates detection of increased m6A levels located in the 3′-untranslated regions (UTR) of the CAP-Gly domain containing linker protein 3 (Clip3) mRNA. The dual-luciferase reporter assay shows that 3′UTR is the direct target of METTL3. Subsequently, the increased m6A modification led to enhanced degradation of mRNA and downregulated CLIP3 expression, eventually resulting in the alleviation of radiation-induced bone injury. Interfering with the METTL3/Clip3 axis can antagonize the effect of CDs, indicating that CDs mediate radiation-induced bone injury via the METTL3/Clip3 axis. Taken together, CDs from L. barbarum alleviate radiation-induced bone injury by inhibiting senescence via regulation of m6A modification of Clip3. The present study paves a new pathway for the management of radiation-induced bone injury.
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Cell Death & Disease
·
2024
·Vol. 15
·期 10
·1-16
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IF 8.1
Wan Xinyi,Zeng Weiwu,Fan Haonan,Wang Chenliang,Han Shixun,Sun Zhongxing,Tang Mei,Shao Juejia,Liu Yu,Fang Yuan,Jia Junqi,Tang Yin,Zhang Yanjun,Zhao Bin,Fang Dong
MAT2B works together with MAT2A to synthesize S-Adenosyl methionine (SAM) as the primary methyl donor. MAT2B, despite lacking catalytic activity, exerts regulatory control over the enzymatic activity of MAT2A. In addition to the enzymatic activity regulation, we find that, in an NADP + -dependent manner, MAT2B binds and stabilizes MAT2A. Disruption of the cellular NADP + remodels the protein level of MAT2A. The pentose phosphatase pathway regulates the level of MAT2A protein through the interaction of NADP + with MAT2B. Additionally, MAT2B-MAT2A interaction regulates the mRNA m6A modification and stability. In liver tumors, the Mat2a mRNA level is elevated but the protein level is decreased by the restricted NADP + . Blocking the interaction between MAT2B and MAT2A by the keto diet can suppress liver tumor growth. These findings reveal that MAT2B is essential for regulating the protein levels of MAT2A and connecting SAM synthesis to mRNA m6A.
研究领域:
癌症生物学
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分子生物学
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生物化学
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Science Advances
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2024
·Vol. 10
·期 40
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IF 11.7
Lian Cui,You Wu,Zeyu Chen,Bingjie Li,Jiangluyi Cai,Zhanhe Chang,Weide Xiao,Yuanyuan Wang,Nan Yang,Yu Wang,Zengyang Yu,Lingling Yao,Rui Ma,Xin Wang,Youdong Chen,Qianyu Chen,Hao Mei,Zhiyi Lan,Yingyuan Yu,Rongfen Chen,Xingbiao Wu,Qian Yu,Jiajing Lu,Ning Yu,Xilin Zhang,Jun Liu,Lingjuan Zhang,Yuping Lai,Shaorong Gao,Yawei Gao,Chunyuan Guo,Yuling Shi
Disrupted N6-methyladenosine (m6A) modification modulates various inflammatory disorders. However, the role of m6A in regulating cutaneous inflammation remains elusive. Here, we reveal that the m6A and its methyltransferase METTL3 are down-regulated in keratinocytes in inflammatory skin diseases. Inducible deletion of Mettl3 in murine keratinocytes results in spontaneous skin inflammation and increases susceptibility to cutaneous inflammation with activation of neutrophil recruitment. Therapeutically, restoration of m6A alleviates the disease phenotypes in mice and suppresses inflammation in human biopsy specimens. We support a model in which m6A modification stabilizes the mRNA of the lipid-metabolizing enzyme ELOVL6 via the m6A reader IGF2BP3, leading to a rewiring of fatty acid metabolism with a reduction in palmitic acid accumulation and, consequently, suppressing neutrophil chemotaxis in cutaneous inflammation. Our findings highlight a previously unrecognized epithelial-intrinsic m6A modification–lipid metabolism pathway that is essential for maintaining epidermal and immune homeostasis and lay the basis for potential therapeutic targeting of m6A modulators to attenuate inflammatory skin diseases.
研究领域:
免疫学
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分子生物学
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皮肤病学
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JOURNAL OF DRUG TARGETING
·
2023
·
IF 4.5
Chen Guo,Mingyi Yu,Jinghua Liu,Zhe Jia,Hui Liu,Shaozhen Zhao
Dry eye disease (DED) is often secondary to diabetes mellitus (DM). We explored the action of Wilms tumor 1-associated protein (WTAP) in DM-DED via lncRNA NEAT1 m6A methylation. DM-DED mouse models were treated with sh-WTAP/sh-NEAT1 plasmid, followed by assessment of corneal epithelial damage/histopathological changes. HCE-2 cells were exposed to hyperosmotic conditions to establish in vitro DED models and treated with oe-NEAT1/sh-NEAT1/sh-WTAP/nigericin (an NLRP3 inflammasome inducer). Cell viability/apoptosis were evaluated by CCK-8/TUNEL. The levels of WTAP/NEAT1/inflammatory factors/NLRP3 inflammasome- and apoptosis-related markers were determined. m6A modification was examined by MeRIP-qPCR and NEAT1 stability was also detected. DM-DED mice exhibited up-regulated WTAP/NEAT1 expression and severe corneal damage, whereas WTAP/NEAT1 knockdown alleviated inflammation/corneal damage. In hyperosmolarity-induced HCE-2 cells, NEAT1 aggravated inflammation and apoptosis, while NEAT1 knockdown suppressed NLRP3 inflammasome activation and ameliorated cell injury. Hyperosmolarity-induced WTAP expression increased m6A modification and NEAT1 mRNA stability. WTAP mediated m6A methylation of NEAT1 and NLRP3 inflammasome activation in DM-DED mice. Collectively, WTAP upregulates NEAT1 expression and facilitates NLRP3 inflammasome activation by increasing m6A methylation, thereby accelerating DM-DED development. WTAP or lncRNA NEAT1 may become a therapeutic target for DM-DED, which offers a theoretical foundation for the investigation and advancement of nanocarrier-based targeted therapeutic medications for DM-DED.
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ADVANCED FUNCTIONAL MATERIALS
·
2025
·
IF 19
Yangcenzi Xie,Wenqian Tian,Chao Zheng,Ming Li
RNA N 6 -methyladenosine (m 6 A) modification plays critical roles in diverse biological processes and human diseases, but its functional studies are greatly impeded by the inability to quantify the m 6 A methylation in whole-transcriptomes. Here, An integrated label-free surface-enhanced Raman spectroscopy (SERS) profiling strategy, named m 6 A-SERS-profiler, is developed for quantitative transcriptome-wide m 6 A detection of cellular and serum RNA. The m 6 A-SERS-profiler is rationally designed through coupling the plasmonic liquid microparticle-based label-free SERS biosensing with the custom deep learning-assisted spectral analysis of m 6 A methylation signatures. With this m 6 A-SERS-profiler, direct identification of SERS spectral signatures of canonical nucleoside monophosphates and N 6 -methyladenosine 5′-monophosphate is achieved. The applicability of the m 6 A-SERS-profiler is verified by quantifying the m 6 A methylation status of microRNA and natural RNA in total RNA isolated from cancer cells and clinical serums. The results reveal a significant difference in the m 6 A RNA methylation among breast cancer cells of different subtypes and between clinical serums from healthy individuals and breast cancer patients. Moreover, the method can quantitatively track the m 6 A dynamics in cancer cells caused by pharmacological inhibition of the m 6 A methyltransferase. Thus, this m 6 A-SERS-profiler holds great promise for transcriptome-wide quantitative detection of m 6 A RNA methylation to investigate biological functions and dynamics of m 6 A methylation in human diseases.
研究领域:
生物化学
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分子生物学
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生物物理学
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癌症研究
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分析化学
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eLife
·
2025
·
IF 0
Chong Zhang,Zuoyan Zhang,Yueyi Wu,Yuchen Wu,Jing Cheng,Kaizhi Luo,Zhidi Li,Manman Zhang,Jian Wang,Xuesen Zhang,Yangling Li
Non-small cell lung cancer (NSCLC) is the most common subtype of lung cancer, and the prognosis is poor due to distant metastasis. Thus, there is an urgent need to discover novel therapeutic targets and strategies to overcome metastasis. A series of in vitro and in vivo phenotype experiments were performed to investigate the role of phosphodiesterase 1A (PDE1A) in NSCLC. The RNA binding protein immunoprecipitation (RIP) assay, messenger RNA (mRNA) stability assay, and LC-MS/MS were performed to investigate the molecular mechanisms of PDE1A in NSCLC progression. PDE1A has been shown to promote metastasis and epithelial-mesenchymal transition (EMT) progression of NSCLC. In addition, NSCLC cells overexpressing PDE1A promoted angiogenesis by regulating exosome release. IL-6/JAK/STAT3 signaling pathway was highly enriched in PDE1A-coexpressed genes, and PDE1A promoted NSCLC metastasis by activating the STAT3 pathway. GO enrichment analysis of PDE1A-interacting genes showed that PDE1A might interact with YTHDF2 and participate in m6A-containing RNA binding. The binding between PDE1A and YTHDF2 was verified, and PDE1A regulated the STAT3 pathway by interacting with YTHDF2. The mechanism of the YTHDF2/PDE1A complex in regulating the STAT3 pathway was predicted by overlapping YTHDF2-interacting RNAs and genes coexpressed with YTHDF2 and STAT3. The interactions between YTHDF2 and target mRNAs were predicted, and there were three predicted targets of YTHDF2 with high scores: NRF2, SOCS2, and MET. Indeed, PDE1A interacted with YTHDF2, destabilized SOCS2, and activated the STAT3 pathway. Mechanistic data uncover a novel PDE1A/YTHDF2/STAT3 axis driving NSCLC metastasis and suggest potential therapeutic strategies for metastatic disease.
研究领域:
癌症生物学
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分子生物学
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细胞生物学
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生物化学
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信号转导
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RNA生物学
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肿瘤学
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2026
·
IF 8.7
Bingbing Sun,Wanwan Zhang,Meisheng Yi,Kuntong Jia
N 6 -methyladenosine (m 6 A) modification plays crucial roles in diverse cellular processes, including the regulation of innate immune responses; however, its specific role in antiviral defense mechanisms in aquatic organisms remains incompletely understood. This study identifies LjMETTL14, a core m 6 A methyltransferase in sea perch ( Lateolabrax japonicus ), as a key regulator of antiviral immunity against nervous necrosis virus (NNV), a major pathogen threatening aquaculture. Our findings show that LjMETTL14 expression was significantly upregulated in response to NNV infection, and overexpression of LjMETTL14 suppresses viral replication by enhancing retinoic acid-inducible gene I-like receptor (RLRs) signaling and type I interferon (IFN) production. In contrast, LjMETTL14 knockdown leads to impaired RLRs signaling and markedly increased viral replication, underscoring its essential antiviral function. Mechanistically, LjMETTL14 interacts specifically with transmembrane domain of mitochondrial antiviral signaling protein (LjMAVS), promoting its m 6 A methylation, protein stability, and multimeric aggregation, thereby enhancing LjMAVS-mediated type I IFN signaling. Conversely, NNV capsid protein (CP) interacts with LjMETTL14, suppressing its expression and impeding the LjMAVS-dependent IFN response, thereby facilitating viral replication. These findings reveal a novel epitranscriptomic regulatory mechanism involving LjMETTL14 and LjMAVS that orchestrates antiviral immunity in fish, highlighting LjMETTL14 as a potential therapeutic target for controlling NNV infection in aquaculture.
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