BREAST CANCER RESEARCH AND TREATMENT
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2025
·Vol. 57
·期 4
·1064
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IF 3
Jie Hu,Qilong Liu,Bi Feng,Yanling Lu,Kai Chen
Purpose Esophageal cancer (EC) is a rapidly progressing malignancy characterized by a low survival rate and limited treatment success, largely due to late-stage detection, frequent recurrence, and a high propensity for metastasis, despite ongoing advances in therapeutic strategies. While oxaliplatin (L-OHP) is a potent chemotherapeutic agent that induces apoptosis in EC cells, its effectiveness is significantly hindered by the development of resistance. Materials and Methods The assessment of gene and protein expression was conducted through a combination of quantitative real-time polymerase chain reaction, Western blot, and immunohistochemical staining. Cell viability was assessed using the cell counting kit-8 assay. The interactions among ALYREF, TBL1XR1, KMT2E, and APOC1 were investigated through RNA immunoprecipitation, chromatin immunoprecipitation (ChIP), ChIP-reChIP, RNA pulldown, and dual-luciferase assays. An in vivo mouse model of EC was established. Results Expression levels of both APOC1 and ALYREF were elevated in L-OHP–resistant EC tissues and cell lines, and their silencing enhanced sensitivity to L-OHP. TBL1XR1 and KMT2E synergistically upregulated APOC1 expression. Moreover, ALYREF recognized the 5-methylcytosine (m5C) sites on TBL1XR1 and KMT2E mRNAs, stabilizing these transcripts and promoting APOC1 expression. The regulatory role of these interactions was further validated in vivo . Conclusion This study demonstrated that ALYREF interacted with the m5C sites on TBL1XR1 and KMT2E mRNAs, enhancing their stability and leading to increased transcription of APOC1, which in turn contributed to L-OHP resistance in EC. These findings suggest that targeting APOC1 could be a promising strategy for overcoming L-OHP resistance in EC.
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2025
·Vol. 16
·期 1
·1-19
·
IF 9.6
Chen Shengjun,Wang Yujie,Zhang Jinjin,Liu Bo,Liu Weili,Cao Guohong,Li Rongrong,Li Hongbo,Zhai Nailiang,Song Xiaodong,Zhang Songzi,Lv Changjun
Fibroblast-to-myofibroblast differentiation is the main cytopathologic characteristic of pulmonary fibrosis. However, its underlying molecular mechanism remains poorly understood. This study elucidated that the nuclear export of lncNONMMUT062668.2 (lnc668) exacerbated pulmonary fibrosis by activating fibroblast-to-myofibroblast differentiation. Mechanistic research revealed that histone H3K9 lactylation in the promoter region of the N6-methyladenosine (m 6 A) writer METTL3 was enriched to enhance METTL3 transcription, leading to the lnc668 m 6 A modification. Meanwhile, the m 6 A reader YTHDC1 recognized m 6 A-modified lnc668 and elevated the METTL3-mediated lnc668 modification. Subsequently, phase-separating YTHDC1 promoted the nuclear export of m 6 A-modified lnc668. In this process, the phase-separating YTHDC1 formed a nuclear pore complex with serine/arginine-rich splicing factor 3, Aly/REF export factor, and exportin-5 to assist the translocation of m 6 A-modified lnc668 from nucleus to cytoplasm. After nuclear export, lnc668 facilitated the translation and stability of its host gene phosphatidylinositol-binding clathrin assembly protein to activate fibroblast-to-myofibroblast differentiation, leading to the aggravation of pulmonary fibrosis, which also depended on YTHDC1 phase separation. This study first clarified that YTHDC1 phase separation is crucial for the m 6 A modification, nuclear export, and profibrotic role of lnc668 in exacerbating pulmonary fibrosis. These findings provide new insights into the nuclear export of cytoplasmic lncRNAs and identified potential targets for pulmonary fibrosis therapy.
研究领域:
分子生物学
·
表观遗传学
·
肺病学
·
RNA生物学
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高影响因子
Journal of Translational Medicine
·
2024
·Vol. 22
·期 1
·1-19
·
IF 6.1
Wang Runze,Xue Wei,Kan Feifei,Zhang Huiying,Wang Di,Wang Lei,Wang Jianwen
Background Diabetic retinopathy (DR) is the leading cause of blinding eye disease among working adults and is primarily attributed to the excessive proliferation of microvessels, which leads to vitreous hemorrhage and retinal traction, thereby significantly impairing patient vision. NSUN2-mediated RNA m 5 C methylation is implicated in various diseases, and in this investigation, we focused on elucidating the impact of NSUN2 on the regulation of the expression of the downstream gene MUC1, specifically through RNA m 5 C methylation, on the progression of DR. Method Utilizing Microarray analysis, we examined patient vitreous fluid to pinpoint potential therapeutic targets for DR. Differential expression of NSUN2 was validated through qRT-PCR, Western blot, and immunofluorescence in human tissue, animal tissue, and cell model of DR. The relationship between NSUN2 and DR was explored in vitro and in vivo through gene knockdown and overexpression. Various techniques, such as MeRIP-qPCR and dot blot, were applied to reveal the downstream targets and mechanism of action of NSUN2. Results The levels of both NSUN2 and RNA m 5 C methylation were significantly elevated in the DR model. Knockdown of NSUN2 mitigated DR lesion formation both in vitro and in vivo. Mechanistically, NSUN2 promoted MUC1 expression by binding to the RNA m 5 C reader ALYREF. Knockdown of ALYREF resulted in DR lesion alterations similar to those observed with NSUN2 knockdown. Moreover, MUC1 overexpression successfully reversed a series of DR alterations induced by NSUN2 silencing. Conclusions NSUN2 regulates the expression of MUC1 through ALYREF-mediated RNA m 5 C methylation, thereby regulating the progression of DR and providing a new option for the treatment of DR in the future.
研究领域:
眼科学
·
分子生物学
·
表观遗传学
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高影响因子
CELLULAR AND MOLECULAR LIFE SCIENCES
·
2026
·
IF 6.5
Siqi Nian,Lulu Zhao,Xiaokang He,Ping Xia,Yanqing Liu,Baotong Hua,Jun Li,Hongxing Zhang
Background: Patients with heart failure (HF) frequently develop atrial fibrillation, but the precise molecular mechanisms are unclear, leading to limited therapeutic strategies. Methods: Isoproterenol hydrochloride (ISO)-induced mouse HF model and ISO-treated HL-1 cardiomyocyte model were employed. A combination of qRT-PCR, Western blot, ChIP, dual-luciferase reporter assay, MeRIP-qPCR, RIP-qPCR, actinomycin D assay, and mitochondrial function assessments were used to systematically investigate the regulatory mechanism of the ALYREF/MZF1/HTRA1 axis and its role in cardiac remodeling and atrial fibrillation susceptibility. Results: HTRA1 expression was elevated in HF mice and human atrial fibrillation data. In cellular models, HTRA1 overexpression induced mitochondrial damage, cellular hypertrophy, and inflammation via the HIF-1α pathway. The transcription factor MZF1 directly bound to and activated the HTRA1 promoter. NSUN2-mediated m5C modification of MZF1 mRNA was required for its recognition and stabilization by the m5C reader protein ALYREF, thereby positively regulating the MZF1/HTRA1 axis. In the ISO-induced HF mouse model, knockdown of ALYREF effectively reduced MZF1 and HTRA1 expression, alleviated myocardial hypertrophy, fibrosis, cardiac dysfunction, and atrial fibrillation inducibility. Conclusion: This study elucidates a novel signaling axis wherein NSUN2-mediated m5C modification of MZF1 mRNA enables its stabilization by ALYREF, leading to transcriptional upregulation of HTRA1. This axis drives cardiomyocyte mitochondrial dysfunction, hypertrophy, and inflammation in the context of HF, ultimately increasing susceptibility to atrial fibrillation.
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高影响因子
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