Molecular Medicine Reports
·
2022
·Vol. 26
·期 1
·1-1
·
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
CHEMICAL ENGINEERING JOURNAL
·
2024
·
IF 13.3
Haiping Li,Yuying Zhang,Bo Huang,Feifei Yang,Qiang Ma,Xiaolin Wang,Yuying Liu,Junwu Ren,Xiaojuan Pan,Ce Liang,Shimin Wang,Hao Ning,Changhong Qin,Yan Jiang,Ai Ran,Bin Xiao
Gastric cancer (GC) is a prevalent malignancy in China, necessitating innovative treatments. Recent advancements in nucleic acid drugs, particularly small interfering RNAs (siRNAs), have shown promise in therapeutic applications. Biodegradable layered double hydroxides (LDHs), as a class of typical two-dimensional (2D) materials, hold great prospects in biomedical and drug delivery systems. Building on our previous research, which identified the upregulated insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) promoted GC progression, we devised a strategy that leverages the unique properties of LDHs carriers with siRNA therapeutics. Herein, we synthesized CuAl-LDHs containing variable valence metal cations (Cu 2+ ), capable of inducing a Fenton-like reaction in the tumor micro-acid environment (TME) of GC. Subsequently, we constructed si-IGF2BP3/CuAl-LDHs nanocomposites to protect and deliver si-IGF2BP3 via the CuAl-LDHs carrier. The obtained nanocomposites demonstrated significant efficacy in inhibiting GC cell proliferation by silencing the IGF2BP3 gene at both the mRNA and protein levels, accelerating oxidative stress in GC cells through a Fenton-like reaction, and achieving greater suppression of tumor volume than CuAl-LDHs alone. The remarkable anti-tumor effect was attributed to the CuAl-LDHs carrier’s superior siRNA immobilization and delivery capabilities, as well as the catalytic ability of Cu in CuAl-LDHs, facilitating the Fenton-like reaction within TME. Overall, this integrated GC therapy strategy employing LDHs nano-carriers may represent a significant advancement in developing next-generation therapeutic systems. It underscores the potential of LDHs as an effective platform for targeted GC therapy.
研究领域:
肿瘤学
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纳米技术
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药物递送系统
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分子生物学
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生物医学工程
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DOI
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2024
·
IF 5.3
Jin Wu,Xiang Li,Hepeng Nie,Yue Shen,Zixiang Guo,Catherine Huihan Chu,Kunzhan Cai,Chunbo Tang
Diabetes-related hyperglycemia inhibits bone marrow mesenchymal stem cell (BMSC) function, thereby disrupting osteoblast capacity and bone regeneration. Dietary supplementation with phytic acid (PA), a natural inositol phosphate, has shown promise in preventing osteoporosis and diabetes-related complications. Emerging evidence has suggested that circular (circ)RNAs implicate in the regulation of bone diseases, but their specific regulatory roles in BMSC osteogenesis in hyperglycemic environments remain elucidated. In this study, in virto experiments demonstrated that PA treatment effectively improved the osteogenic capability of high glucose-mediated BMSCs. Differentially expressed circRNAs in PA-induced BMSCs were identified using circRNA microarray analysis. Here, our findings highlight an upregulation of circEIF4B expression in BMSCs stimulated with PA under a high-glucose microenvironment. Further investigations demonstrated that circEIF4B overexpression promoted high glucose-mediated BMSC osteogenesis . In contrast, circEIF4B knockdown exerted the opposite effect. Mechanistically, circEIF4B sequestered microRNA miR-186-5p and triggered osteogenesis enhancement in BMSCs by targeting FOXO1 directly. Furthermore, circEIF4B inhibited the ubiquitin-mediated degradation of IGF2BP3, thereby stabilizing ITGA5 mRNA and promoting BMSC osteogenic differentiation. In vivo experiments, circEIF4B inhibition attenuated the effectiveness of PA treatment in diabetic rats with cranial defects. Collectively, our study identifies PA as a novel positive regulator of BMSC osteogenic differentiation through the circEIF4B/miR-186-5p/FOXO1 and circEIF4B/IGF2BP3/ITGA5 axes, which offers a new strategy for treating high glucose-mediated BMSC osteogenic dysfunction and delayed bone regeneration in diabetes.
研究领域:
干细胞生物学
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分子生物学
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糖尿病研究
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骨再生
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RNA生物学
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DOI
PubMed
高影响因子
Cell Death & Disease
·
2024
·Vol. 15
·期 12
·1-16
·
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
JOURNAL OF NANOBIOTECHNOLOGY
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2024
·Vol. 22
·期 1
·1-21
·
IF 10.6
Yu Jiang,Gao Yidan,Liu Fei,Zhang Yuyu,Li Jianda,Ding Luogang,Ren Sufang,Yang Jie,Jiao Jian,Feng Gong,Chen Zhi,Sun Wenbo,Wu Jiaqiang
Background Animal and human health are seriously threatened by bacterial infections, which can lead to bacteremia and extremely high rates of morbidity and mortality. Recently, there have been reports indicating the involvement of exosomal circular RNAs (circRNAs) in a range of human disorders and tumor types. However, the role of exosomal circRNAs in bacterial infection remains elusive. Methods We extracted and identified exosomes from the culture medium of PIEC cells infected with or without Glaesserella parasuis . RNA sequencing analysis was performed on the exosomes to screen and identify circRNAs (circHIF1α) associated with Glaesserella parasuis infection. PIEC cells were infected with Staphylococcus aureus or Streptococcus suis 2 to further determine whether exosome-derived circHIF1α was the crucial circHIF1α associated with bacterial infections. The transmission process of exosomes and their circHIF1α between cells was clarified via exosome tracing and co-culture assay. Moreover, the mechanism of circHIF1α being packaged into exosomes was explored, and the effects of exosomes and their circHIF1α on cell proliferation, DNA damage and cell cycle were analyzed. In addition, the binding mode and site of interacting proteins with circHIF1α were further determined. In vivo and in vitro, the role of exosomes and their circHIF1α in host resistance to bacterial infection was confirmed. Results We first discovered a new circHIF1α that was very stable and detectable, encapsulated into exosomes by hnRNPA2B1, and whose expression in exosomes of bacterially infected PIEC cells significantly decreased. Additionally, exosomal circHIF1α reduced bacterial infection both in vitro and in vivo and suppressed the growth of reception cells. Mechanistically, the circHIF1α interacted with the KH domain of IGF2BP3 in an m6A-modified manner, which mediated DNA damage to arrest the cells at the G1/S phase through the interaction between the regulator of Chromosome Condensation 2 (RCC2) and γ-H2AX protein. Exosomal circHIF1α is a unique therapeutic target for bacterial infection since this work highlights its critical function in fighting bacterial infection.
研究领域:
分子生物学
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微生物学
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细胞生物学
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传染病学
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产品关联
DOI
PubMed
高影响因子
MOLECULAR AND CELLULAR BIOCHEMISTRY
·
2026
·
IF 4.7
Yang Chunyan,Chen Bin,Jing Haiqing,Liu Qing,Wang Yanqiong,Wu Yanrui,Song Jiayi,Fu Yi
Angiogenesis plays a significant role in the progression of idiopathic pulmonary fibrosis (IPF). The RNA-binding protein IGF2BP3 is associated with fibrosis and angiogenesis, but its role in IPF angiogenesis remain unclear. Additionally, Tianlongjie (TL) has been confirmed to inhibit IPF progression, but the role of IGF2BP3 in this process also needs to be elucidated. A bleomycin (BLM)-induced pulmonary fibrosis rat model was established via intratracheal instillation of BLM, and an angiogenesis cell model was constructed by treating HPMVECs with VEGF165. HE staining was used to detect lung tissue injury. Masson staining, HYP content measurement, Western blot, and Immunohistochemistry assessed to evaluate fibrosis and angiogenesis progression. EdU staining was employed to detect cell proliferation. RIP-qPCR and dual-luciferase reporter assays were performed to examine the interaction between IGF2BP3 and HIF-1α. IGF2BP3 was abnormally highly expressed in pulmonary fibrosis. IGF2BP3 knockdown reduced the expression of HYP, COL-I, COL-III, α-SMA, CD31, CD34, and VEGFA in pulmonary fibrosis rat lung tissues, increased E-cadherin expression, and inhibited pulmonary fibrosis progression and microvascular formation in rats. In vitro, IGF2BP3 knockdown suppressed cell proliferation, migration and vascular endothelial cell angiogenesis. Mechanistically, IGF2BP3 may promote HIF-1α stability through m 6 A modification, and HIF-1α overexpression attenuated the inhibitory effect of IGF2BP3 knockdown on angiogenesis. Furthermore, TL treatment was associated with reduced fibrosis and lower IGF2BP3/HIF-1α expression. In conclusion, IGF2BP3 can promote pulmonary fibrosis-related angiogenesis by stabilizing HIF-1α expression, and TL inhibits IGF2BP3 and HIF-1α expression, angiogenesis and fibrosis progression in pulmonary fibrosis rats.
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DOI
高影响因子
PLoS One
·
2024
·Vol. 19
·期 8
·e0306043
·
IF 2.9
Yuping Liao,Feng Zhang,Fang Yang,Shijin Huang,Sha Su,Xuemei Tan,Linlin Zhong,Lingjie Deng,Lihong Pang
Background
Haemoglobin H (HbH) disease is caused by a disorder of α-globin synthesis, and it results in a wide range of clinical symptoms. M 6 A methylation modification may be one of the mechanisms of heterogeneity. Therefore, this article explored the role of methyltransferase like 16 (METTL16) in HbH disease.
Method
The results of epigenetic transcriptome microarray were analysed and verified through bioinformatic methods and qRT-PCR, respectively. The overexpression or knock down of METTL16 in K562 cells was examined to determine its role in reactive oxygen species (ROS), cell cycle processes or iron overload. YTH domain family protein 3 (YTHDF3) was knocked down in K562 cells and K562 cells overexpressing METTL16 via siRNA to investigate its function. In addition, haemoglobin expression was detected through benzidine staining. qRT-PCR, WB, methylated RNA Immunoprecipitation (MeRIP) and (RNA Immunoprecipitation) RIP experiments were conducted to explore the mechanism of intermolecular interaction.
Results
METTL16, YTHDF3 and solute carrier family 5 member 3 (SLC5A3) mRNA and the methylation level of SLC5A3 mRNA were downregulated in HbH patients. Insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) mRNA expression was negatively correlated with HGB content among patients with HbH-CS disease. Overexpression of METTL16 increased ROS and intracellular iron contents in K562 cells, changed the K562 cell cycle, reduced hemin-induced haemoglobin synthesis, increased the expressions of SLC5A3 and HBG and increased SLC5A3 mRNA methylation levels. Knockdown of METTL16 reduced ROS and intracellular iron contents in K562 cells. Hemin treatment of K562 cells for more than 14 days reduced the protein expressions of METTL16 and SLC5A3 and SLC5A3 mRNA methylation levels. Knockdown of YTHDF3 rescued the intracellular iron content changes induced by the overexpression of METTL16. The RIP experiment revealed that SLC5A3 mRNA can be enriched by METTL16 antibody.
Conclusion
METTL16 may affect the expression of SLC5A3 by changing its m 6 A modification level and regulating ROS synthesis, intracellular iron and cycle of red blood cells. Moreover, METTL16 possibly affects the expression of haemoglobin through IGF2BP3, which regulates the clinical phenotype of HbH disease.
研究领域:
分子生物学
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血液学
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表观遗传学
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细胞生物学
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DOI
PubMed
高影响因子
ACTA PHARMACOLOGICA SINICA
·
2026
·
IF 10.4
Xu Lu,Ma Yan,Yao Wang,Qiu Ya-ju,Xu Chao,Xu Fang-yue,Zou Zhi-miao,Dai Wu-min,Gong Wan-gang,Ma De-ning,Chen Xiao-wan,Ye Wen-kai,Huang Yi-yun,Chen Hai-tao,Hong Lue,Mo Jia-ping,Feng Jian-guo,Yu En-yan,Chen Wei,Zhang Yu-hua,Yao Qing-hua,Li Xia
5-Fluorouracil (5-FU) resistance in colorectal cancer (CRC) involves oxidative stress mechanisms, but the role of epitranscriptomic regulation remains unclear. This study investigates how oxidative post-translational modifications of the N6-methyladenosine (m 6 A) methyltransferase METTL16 contribute to 5-FU resistance. Parental (HCT8, HCT15) and 5-FU-resistant CRC cells were compared using redox proteomics, m 6 A-seq, RNA-seq, and functional assays. METTL16 S-glutathionylation was assessed via streptavidin pulldown and mass spectrometry. IGF2BP3’s role was validated through knockdown/overexpression, patient-derived organoids (PDOs), and xenograft models. Clinical relevance was evaluated in 112 CRC patient tissues and data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Drug synergy was tested using isoliquiritigenin (ISO) combined with 5-FU. Resistant cells exhibited elevated global protein S-glutathionylation and reduced m 6 A RNA methylation. METTL16 underwent site-specific S-glutathionylation at Cys548, leading to its degradation and subsequent m 6 A loss. Integrative omics identified IGF2BP3 as a key METTL16 target: reduced m 6 A on IGF2BP3 mRNA enhanced its nuclear export, splicing, and overexpression. IGF2BP3 knockdown sensitized resistant cells to 5-FU in vitro and in vivo, while overexpression conferred resistance. Mechanistically, IGF2BP3 destabilized CFTR mRNA (an ABC transporter), reducing 5-FU uptake. Clinically, high IGF2BP3 correlated with poor survival and 5-FU resistance in CRC patients. Targeting IGF2BP3 with ISO synergized with 5-FU, overcoming resistance in cells and xenografts. Oxidative stress-induced METTL16 S-glutathionylation drives 5-FU resistance by reducing m 6 A modification, enabling IGF2BP3 overexpression and CFTR suppression. IGF2BP3 is a biomarker of clinical resistance, and its targeting with ISO represents a promising combinatorial strategy to restore 5-FU efficacy in CRC.
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DOI
PubMed
高影响因子
Science Advances
·
2024
·Vol. 10
·期 40
·
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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DOI
PubMed
高影响因子
Journal of Translational Medicine
·
2025
·Vol. 23
·期 1
·1-19
·
IF 7.5
Hu Songliu,Zhan Ning,Li Jian,Wang Liqun,Liu Yiyan,Jin Ke,Wang Yixuan,Zhang Juxuan,Chen Yiyang,Bai Yang,Wang Yichong,Qi Lishuang,Liu Shilong
Background Radiotherapy is commonly used for locoregionally advanced NSCLC, but radioresistance is a clinical challenge. The long non-coding RNA CBR3-AS1 mediates radioresistance in NSCLC, yet the underlying molecular mechanism is unclear. This study aims to explore whether and how N6-methyladenosine (m6A) modification regulates CBR3-AS1 expression and promotes NSCLC radioresistance. Methods Integrative bioinformatics analyses were used to investigate the m6A methyltransferases that were associated with CBR3-AS1 expression and radioresistance of patients using data from The Cancer Genome Atlas of lung adenocarcinoma and squamous cell carcinoma. Clinical samples of 133 patients with NSCLC was collected to validate the correlation of the methyltransferase with radioresistance. The functional role and molecular mechanism of the methyltransferase in radioresistance was investigated through a series of in vitro experiments including m6A MeRIP-PCR, lentivirus transfection, RNA immunoprecipitation, Luciferase reporter, Colony formation, Transwell invasion, Flow cytometry, ELISA and TUNEL assay and in vivo experiments. Results The methyltransferase RNA binding motif protein 15 (RBM15) was identified as it was significantly positively correlated with CBR3-AS1 expression and overall survival of NSCLC patients receiving radiotherapy. The clinical samples demonstrated that the high protein expression of RBM15 was significantly enriched in patients with radioresistance as well as associated with poor prognosis of patients receiving radiotherapy. In vitro, RBM15 silencing enhanced the effects of radiation on the growth and invasion inhibition, and apoptosis induction of NSCLC cells; RBM15 overexpression had the opposite effects. Mechanistically, RBM15 induced CBR3-AS1 upregulation via an m6A-IGF2BP3-dependent mechanism, inducing CXCL1 expression by sponging miR-409-3p to recruit myeloid-derived suppressor cells (MDSCs) and inhibit T cell activity. In vivo, RBM15 silencing suppressed MDSC invasiveness and enhanced CD8 + and CD4 + T cell infiltration, causing NSCLC cells to overcome radioresistance. Conclusion Our study identifies methyltransferase RBM15 as a potential therapeutic target for NSCLC radioresistance whose inhibition reverses resistance through limiting MDSC recruitment via the m6A-IGF2BP3-CBR3-AS1/miR-409-3p/CXCL1 axis. Graphical
研究领域:
肿瘤学
·
分子生物学
·
表观遗传学
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产品关联
DOI
PubMed
高影响因子
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