TOXICOLOGY
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2024
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IF 4.8
Jingyu Wang,Xiaoli Guo,Yujiao Chen,Wei Zhang,Jing Ren,Ai Gao
Benzene exposure leads to hematotoxicity, and epigenetic modification is considered to be a potential mechanism of benzene pathogenesis. As a newly discovered post-transcriptional modification, the roles of N6-methyladenosine (m6A) in benzene hematotoxicity are still unclear. m6A can only exert its gene regulatory function after being recognized by m6A reading proteins. In this study, we found that the expression of m6A reader IGF2BP1 decreased in benzene poisoning workers and in 20 μM benzene metabolite 1,4-BQ-treated AHH-1 cells. Further overexpression of IGF2BP1 in mice alleviated 50 ppm benzene-induced hematopoietic damage, suggesting that IGF2BP1 plays a critical role in benzene hematotoxicity. Next, we examined transcriptome-wide m6A methylation in vitro to search for target genes of IGF2BP1. We found that benzene metabolite 1,4-BQ treatment altered the m6A methylation levels of various genes. The comprehensive analysis of mRNA expression and m6A methylation uncovered that the hypomethylated Ribosomal Protein L36 (RPL36) and its consequent reduced expression impaired cell proliferation. Mechanically, m6A modification reduced RNA stability to down-regulate RPL36 expression. Moreover, overexpression of IGF2BP1 relieved RPL36 reduction and cell proliferation inhibition caused by benzene in vitro and in vivo by directly binding with RPL36 mRNA. In conclusion, the m6A reader IGF2BP1 attenuates the stability of RPL36 and cell proliferation to mediate benzene hematotoxicity by recognizing m6A modification. IGF2BP1 and RPL36 may be key molecules and potential therapeutic targets for benzene hematotoxicity.
研究领域:
毒理学
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分子生物学
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表观遗传学
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DOI
PubMed
高影响因子
Molecular Medicine Reports
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2022
·Vol. 26
·期 1
·1-1
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IF 3.423
Jinbiao Han,Xia Hu
The mortality rate of ovarian cancer (OC) is the highest among the different types of female reproductive system cancers. SIX homeobox 4 (SIX4), a member of the homeobox family, subfamily SIX, fulfills an important role in metastasis and angiogenesis in a variety of types of cancer. The aim of the present study was to investigate both the effects and the underlying mechanism of SIX4 on angiogenesis in OC. The Gene Expression Profiling Interactive Analysis and Encyclopedia of RNA Interactomes databases were employed to predict the expression levels of SIX4 in OC tissues, and its association with the overall survival (OS) rate of patients with OC. The expression levels of SIX4 in OC cell lines were detected by reverse transcription‑quantitative PCR (RT‑qPCR) and western blot analysis. Following silencing of SIX4, the proliferation, invasion, migration and angiogenesis of OC cells were investigated via Cell Counting Kit‑8, colony formation, wound healing, Transwell and tube formation assays. Subsequently, the levels of insulin‑like growth factor 2 mRNA binding protein 3 (IGF2BP3) in OC cell lines were detected by RT‑qPCR and western blot analysis. The ability of IGF2BP3 to bind to SIX4 mRNA was detected via an RNA immunoprecipitation assay, and the stability of SIX4 mRNA was assessed by RT‑qPCR following Actinomycin D treatment. Finally, the effects of transfection of sh‑SIX4 and overexpression of IGF2BP3 simultaneously were examined to further delineate the mechanism involved. It was revealed that SIX4 was highly expressed in OC tissues and cells, and its expression was associated with low OS rates in patients with OC. SIX4 knockdown with short hairpin RNA inhibited the proliferation, migration and invasion of cells, as well as angiogenesis. In addition, IGF2BP3 overexpression led to an improvement in the stability of SIX4 mRNA. Overexpression of IGF2BP3 also reversed the inhibitory effect of SIX4 interference on the malignant phenotypes of OC cells. Taken together, the results of the present study demonstrated that IGF2BP3‑stabilized SIX4 promoted the proliferation, metastasis and angiogenesis of SKOV3 cells.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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DOI
PubMed
高影响因子
Cancer & Metabolism
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2025
·Vol. 13
·期 1
·1-17
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IF 5.3
Li Hao,Gong Tingyue,Zhao Yongheng,Luo Yang,Tang Shuibin,Wang Tingfeng,Lin Haiping,Zhong Ming
Purpose Cancer cells rely on serine biosynthesis for growth, but its regulation in colorectal cancer (CRC) remains not well understood. This study identifies the m 5 C methyltransferase NSUN2 (NOP2/Sun domain family, member 2) as a key regulator of serine biosynthesis, revealing a novel mechanism driving CRC progression. Methods The expression and prognostic value of NSUN2 were evaluated using bioinformatics analyses and immunohistochemistry (IHC) assays. The effects of NSUN2 on cellular serine biosynthesis, intracellular reactive oxygen species (ROS) levels, and apoptosis levels were analyzed both in vitro and in vivo. Additionally, RNA sequencing, Methylated RNA Immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP), and RNA stability assays were utilized to screen and validate the association between NSUN2 and phosphoglycerate dehydrogenase (PHGDH). Results NSUN2 was found to be highly expressed in CRC and associated with poor patient survival. PHGDH, a direct downstream target of NSUN2, plays a crucial role in NSUN2-mediated serine biosynthesis. Furthermore, inhibition of NSUN2 significantly reduced the intracellular NADH/NAD + and NADPH/NADP + ratios, leading to an increase in ROS levels and apoptosis levels, thereby inhibiting CRC progression. Additionally, NSUN2 enhances PHGDH expression and mRNA stability by binding to the “reader” protein m 5 C-Aly/REF export factor (ALYREF). Conclusions This study identified a novel NSUN2/ALYREF/m 5 C-PHGDH axis might be promising therapeutic targets for CRC.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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RNA生物学
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代谢调控
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DOI
PubMed
高影响因子
EXPERIMENTAL EYE RESEARCH
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2024
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IF 3
Di Li,Xuanyi Che,Ningning Gao,Jing Li
Previous studies have shown that the development of age-related cataract (ARC) is involved in lens epithelium dysfunction, which is associated with abnormally expressed circular RNAs (circRNAs). The current work aims to probe the role of circSTRBP (hsa_circ_0088,427) in hydrogen peroxide (H 2 O 2 )-induced lens epitheliums. Lens epithelium tissues were harvested from ARC or normal subjects (n = 23). CircSTRBP, spermatid perinuclear RNA binding protein (STRBP), and nicotinamide adenine dinucleotide phosphate oxidase subunit 4 (NOX4) levels were measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR). Cell proliferation, cycle progression, and apoptosis were assessed using 5-ethynyl-2′-deoxyuridine (EdU), Cell Counting Kit-8 (CCK-8), and flow cytometry assays. Caspase 3 activity, reactive oxygen species (ROS), malondialdehyde (MDA), and Glutathione peroxidases (GSH-PX) levels were detected using corresponding kits. NOX4 protein level was determined using Western blot. The interaction between insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) and circSTRBP or NOX4 was assessed through RNA immunoprecipitation (RIP). CircSTRBP and NOX4 abundances were increased in lens epithelium samples from ARC patients and H 2 O 2 -treated SRA01/04 cells. CircSTRBP knockdown might abolish H 2 O 2 -triggered SRA01/04 cell proliferation repression and apoptosis and oxidative stress promotion. In mechanism, circSTRBP is bound with IGF2BP1 and improves the stability and expression of NOX4 mRNA in SRA01/04 cells. CircSTRBP facilitated H 2 O 2 -induced SRA01/04 cell apoptosis and oxidative stress through by enhancing NOX4 mRNA stability via recruiting IGF2BP1, providing novel insights for ARC progression and treatment.
研究领域:
分子生物学
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细胞生物学
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眼科学
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生物化学
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DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
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2020
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IF 5.186
Zhang Yan,Wang Yanfei,Yao Xuebo,Wang Changquan,Chen Fangyi,Liu Dong,Shao Ming,Xu Zhigang
Hair cells in the inner ear and lateral lines are mechanosensitive receptor cells whose development and function are tightly regulated. Several transcription factors as well as splicing factors have been identified to play important roles in hair cell development, whereas the role of RNA stability in this process is poorly understood. In the present work, we report that RNA-binding motif protein 24a (Rbm24a) is indispensable for hair cell development in zebrafish. Rbm24a expression is detected in the inner ear as well as lateral line neuromasts. Albeit rbm24a deficient zebrafish do not survive beyond 9 days post fertilization (dpf) due to effects outside of the inner ear, rbm24a deficiency does not affect the early development of inner ear except for delayed otolith formation and semicircular canal fusion. However, hair cell development is severely affected and hair bundle is disorganized in rbm24a mutants. As a result, the auditory and vestibular function of rbm24a mutants are compromised. RNAseq analyses identified several Rbm24a-target mRNAs that are directly bound by Rbm24a and are dysregulated in rbm24a mutants. Among the identified Rbm24a-target genes, lrrc23, dfna5b, and smpx are particularly interesting as their dysregulation might contribute to the inner ear phenotypes in rbm24a mutants. In conclusion, our data suggest that Rbm24a affects hair cell development in zebrafish through regulating mRNA stability.
研究领域:
发育生物学
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分子生物学
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神经科学
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遗传学
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DOI
PubMed
高影响因子
Cell Death & Disease
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2024
·Vol. 15
·期 12
·1-16
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IF 8.1
Hou Rui,Sun Xinrui,Cao Shiyao,Wang Yadong,Jiang Luo
The metabolic reprogramming in high-grade serous ovarian carcinoma (HGSOC) affects the tumor stemness, which mediates tumor recurrence and progression. Knowledge of the stemness and metabolic characteristics of HGSOC is insufficient. Squalene epoxidase (SQLE), a key enzyme in cholesterol metabolism, was significantly upregulated in HGSOC samples with a fold change of about 4 in the RNA sequencing analysis. SQLE was positively related to peritoneal metastasis and poor prognosis of HGSOC patients. Functionally, SQLE drove cancer cell proliferation and inhibited apoptosis to accelerate HGSOC growth. SQLE was highly expressed in ALDH + CD133 + FACS-sorted cells derived from HGSOC cells and ovarian cancer stem cells (OCSCs)-enriched tumorspheres. SQLE overexpression resulted in enhanced CSC-like properties, including increased tumorsphere formation and stemness markers expression. In vivo, SQLE not only promoted cell line-derived xenografts growth but extended the OCSCs subpopulation of single-cell suspension. Moreover, non-targeted metabolomics profiling from UPLC-MS/MS system identified 90 differential metabolites responding to SQLE overexpression in HGSOC cells. Among them, the dysfunctional metabolisms of cholesterol and glutathione were involved in the maintenance of HGSOC stemness. Previous studies showed the alteration of N6-Methyladenosine (m6A) modification in HGSOC development. Herein, the m6A modification in the 3’UTR and CDS regions of SQLE mRNA was increased due to upregulated methyltransferases WTAP and downregulated demethylases FTO, which was recognized by m6A-binding proteins IGF2BP3, rather than IGF2BP1 or IGF2BP2, thereby stabilizing the SQLE mRNA. These results suggested that SQLE was a novel potential clinical marker for predicting the HGSOC development and prognosis, as well as a potential therapeutic target of HGSOC.
研究领域:
肿瘤学
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分子生物学
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代谢组学
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癌症生物学
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表观遗传学
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产品关联
DOI
PubMed
高影响因子
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