BACKGROUND Gastric cancer(GC)remains one of the leading causes of cancer-related mortality globally and is associated with poor patient prognosis,which highlights an urgent need to identify effective biomarkers and th...BACKGROUND Gastric cancer(GC)remains one of the leading causes of cancer-related mortality globally and is associated with poor patient prognosis,which highlights an urgent need to identify effective biomarkers and therapeutic targets.N6-methyladenosine(m6A)modification and its reader proteins play a crucial role in tumorigenesis.Insulin-like growth factor 2 mRNA-binding protein 1(IGF2BP1)participates in carcinogenesis and serves as a reader of m6A.However,its exact function and the underlying molecular mechanisms in the progression of GC remain unknown.AIM To investigate the role of IGF2BP1 in the progression of GC.METHODS The IGF2BP1 expression in GC tissues was assessed via immunohistochemistry and correlated with clinicopathological characteristics.Gain-of-function and loss of-function experiments were performed to explore the functional roles of IGF2BP1 and its potential downstream target in GC cells and a nude mouse xenograft model.Cell proliferation,migration,and invasion were assessed using cell counting kit-8,wound-healing,and Transwell assays.RNA sequencing,methylated RNA immunoprecipitation quantitative polymerase chain reaction,and dual-luciferase reporter assays were conducted to elucidate the molecular mechanisms involved.RESULTS The IGF2BP1 was significantly upregulated in GC tissues and was positively associated with lymph node metastasis and poor overall survival.Functionally,IGF2BP1 knockdown inhibited GC cell proliferation,migration,and invasion in vitro and attenuated tumor growth in vivo.Integrated multi-omics analysis identified heparan sulfate 6-O-sulfotransferase 2(HS6ST2)as a key downstream target of IGF2BP1.IGF2BP1 recognized and bound to m6A-modified sites within HS6ST2 mRNA,thereby enhancing its stability in an m6A-dependent manner.Rescue experiments confirmed that HS6ST2 mediated the oncogenic effects of IGF2BP1.Additionally,HS6ST2 knockdown inhibited the malignant characteristics of GC cells and triggered apoptosis,which was associated with inactivation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.CONCLUSION These findings demonstrated that IGF2BP1 drives GC progression by stabilizing HS6ST2 mRNA via m6A modification.The IGF2BP1/HS6ST2 axis may serve as a potential prognostic biomarker and therapeutic intervention for GC.展开更多
Interleukin-33(IL-33)是一种炎症和免疫调节细胞因子,其细胞膜结合形式或可溶性形式在组织损伤、炎症反应和修复等多种生理和病理过程中发挥重要作用。生长刺激表达基因2(ST2,也称为IL-1 receptor accessory protein 1)是其唯一的特异...Interleukin-33(IL-33)是一种炎症和免疫调节细胞因子,其细胞膜结合形式或可溶性形式在组织损伤、炎症反应和修复等多种生理和病理过程中发挥重要作用。生长刺激表达基因2(ST2,也称为IL-1 receptor accessory protein 1)是其唯一的特异性受体,介导IL-33的下游信号转导。近年来,越来越多的研究证据表明IL-33/ST2信号通路与心血管疾病的发生、发展密切相关,包括动脉粥样硬化、心力衰竭、心肌损伤以及冠心病钙化等。本文旨在探讨IL-33/ST2信号通路的生物学特性、激活与调控机制,重点阐述其在心血管疾病,特别是冠心病钙化中的循证医学证据,并探讨其作为生物标志物的应用前景及其在治疗干预中的靶点潜力,为IL-33/ST2信号通路在心血管疾病领域的后续研究、临床转化提供全面且有价值的参考依据。展开更多
IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis.However,their involvement in optic neuropathy due to trauma and glaucoma remains unclear.Here,we report that IL-33 and ST2 were highly exp...IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis.However,their involvement in optic neuropathy due to trauma and glaucoma remains unclear.Here,we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina.Deletion of IL-33 or ST2 exacerbated retinal ganglion cell(RGC)loss,retinal thinning,and nerve fiber degeneration following optic nerve(ON)injury.This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33-/-mice.In vitro,rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors,thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants.Exogenous IL-33 treatment improved RGC survival in Il33-/-and WT mice after ON injury,but not in ST2-/-mice.Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.展开更多
Objective:Suppression of tumorigenicity 2(ST2),the receptor for interleukin(IL)-33,has a critical role in tumor growth,angiogenesis,metastasis,and immune modulation.The IL-33/ST2 pathway is known to influence the pola...Objective:Suppression of tumorigenicity 2(ST2),the receptor for interleukin(IL)-33,has a critical role in tumor growth,angiogenesis,metastasis,and immune modulation.The IL-33/ST2 pathway is known to influence the polarization and function of macrophages,which is integral to modulating the tumor microenvironment.However,the precise role of IL-33/ST2 in tumors,particularly non-small cell lung cancer(NSCLC),has not been established.Methods:ST2 expression in NSCLC was analysed using a murine model and patient specimens.The effect of the IL-33/ST2 axis on macrophage polarization in NSCLC was determined.Results:Elevated ST2 expression was correlated with aggressive tumor growth.Specifically,ST2 expression on macrophages was associated with lung cancer progression and the absence of ST2 on macrophages was associated with diminished tumor growth.IL-33 promoted polarization of alternatively activated macrophages in an ST2-dependent manner that was mediated via the PI3K/Akt signalling pathway.Moreover,IL-33 inhibited T-cell function by inducing the secretion of transforming growth factorβfrom alternatively activated macrophages.Conclusions:Macrophages expressing ST2 can serve as promising therapeutic targets for NSCLC immunotherapy,highlighting the IL-33/ST2 axis as a potential target for future antitumor strategies.展开更多
基金Supported by National Natural Science Foundation of China,No.82570702“Pioneer”and“Leading Goose”Research and Development Program of Zhejiang,No.2025C02139+3 种基金Zhejiang Clinovation Pride,No.CXTD202502030Medical Science and Technology Project of Zhejiang Province,No.2025KY1818 and 2023KY1312Science and Technology Plan Project of Taizhou,No.22ywb09the Major Projects of Taizhou Enze Medical Center,No.2025EZZD02.
摘要BACKGROUND Gastric cancer(GC)remains one of the leading causes of cancer-related mortality globally and is associated with poor patient prognosis,which highlights an urgent need to identify effective biomarkers and therapeutic targets.N6-methyladenosine(m6A)modification and its reader proteins play a crucial role in tumorigenesis.Insulin-like growth factor 2 mRNA-binding protein 1(IGF2BP1)participates in carcinogenesis and serves as a reader of m6A.However,its exact function and the underlying molecular mechanisms in the progression of GC remain unknown.AIM To investigate the role of IGF2BP1 in the progression of GC.METHODS The IGF2BP1 expression in GC tissues was assessed via immunohistochemistry and correlated with clinicopathological characteristics.Gain-of-function and loss of-function experiments were performed to explore the functional roles of IGF2BP1 and its potential downstream target in GC cells and a nude mouse xenograft model.Cell proliferation,migration,and invasion were assessed using cell counting kit-8,wound-healing,and Transwell assays.RNA sequencing,methylated RNA immunoprecipitation quantitative polymerase chain reaction,and dual-luciferase reporter assays were conducted to elucidate the molecular mechanisms involved.RESULTS The IGF2BP1 was significantly upregulated in GC tissues and was positively associated with lymph node metastasis and poor overall survival.Functionally,IGF2BP1 knockdown inhibited GC cell proliferation,migration,and invasion in vitro and attenuated tumor growth in vivo.Integrated multi-omics analysis identified heparan sulfate 6-O-sulfotransferase 2(HS6ST2)as a key downstream target of IGF2BP1.IGF2BP1 recognized and bound to m6A-modified sites within HS6ST2 mRNA,thereby enhancing its stability in an m6A-dependent manner.Rescue experiments confirmed that HS6ST2 mediated the oncogenic effects of IGF2BP1.Additionally,HS6ST2 knockdown inhibited the malignant characteristics of GC cells and triggered apoptosis,which was associated with inactivation of the phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin signaling pathway.CONCLUSION These findings demonstrated that IGF2BP1 drives GC progression by stabilizing HS6ST2 mRNA via m6A modification.The IGF2BP1/HS6ST2 axis may serve as a potential prognostic biomarker and therapeutic intervention for GC.
摘要Interleukin-33(IL-33)是一种炎症和免疫调节细胞因子,其细胞膜结合形式或可溶性形式在组织损伤、炎症反应和修复等多种生理和病理过程中发挥重要作用。生长刺激表达基因2(ST2,也称为IL-1 receptor accessory protein 1)是其唯一的特异性受体,介导IL-33的下游信号转导。近年来,越来越多的研究证据表明IL-33/ST2信号通路与心血管疾病的发生、发展密切相关,包括动脉粥样硬化、心力衰竭、心肌损伤以及冠心病钙化等。本文旨在探讨IL-33/ST2信号通路的生物学特性、激活与调控机制,重点阐述其在心血管疾病,特别是冠心病钙化中的循证医学证据,并探讨其作为生物标志物的应用前景及其在治疗干预中的靶点潜力,为IL-33/ST2信号通路在心血管疾病领域的后续研究、临床转化提供全面且有价值的参考依据。
基金supported by the National Natural Science Foundation of China(31670876 and 82171761).
摘要IL-33 and its receptor ST2 play crucial roles in tissue repair and homeostasis.However,their involvement in optic neuropathy due to trauma and glaucoma remains unclear.Here,we report that IL-33 and ST2 were highly expressed in the mouse optic nerve and retina.Deletion of IL-33 or ST2 exacerbated retinal ganglion cell(RGC)loss,retinal thinning,and nerve fiber degeneration following optic nerve(ON)injury.This heightened retinal neurodegeneration correlated with increased neurotoxic astrocytes in Il33-/-mice.In vitro,rIL-33 mitigated the neurotoxic astrocyte phenotype and reduced the expression of pro-inflammatory factors,thereby alleviating the RGC death induced by neurotoxic astrocyte-conditioned medium in retinal explants.Exogenous IL-33 treatment improved RGC survival in Il33-/-and WT mice after ON injury,but not in ST2-/-mice.Our findings highlight the role of the IL-33/ST2 axis in modulating reactive astrocyte function and providing neuroprotection for RGCs following ON injury.
基金supported by the National Key R&D Program of China(2023YFC2413100)the National Natural Science Foundation of China(No.81501423)the Fundamental Research Funds for the Central Universities。
摘要Objective:Suppression of tumorigenicity 2(ST2),the receptor for interleukin(IL)-33,has a critical role in tumor growth,angiogenesis,metastasis,and immune modulation.The IL-33/ST2 pathway is known to influence the polarization and function of macrophages,which is integral to modulating the tumor microenvironment.However,the precise role of IL-33/ST2 in tumors,particularly non-small cell lung cancer(NSCLC),has not been established.Methods:ST2 expression in NSCLC was analysed using a murine model and patient specimens.The effect of the IL-33/ST2 axis on macrophage polarization in NSCLC was determined.Results:Elevated ST2 expression was correlated with aggressive tumor growth.Specifically,ST2 expression on macrophages was associated with lung cancer progression and the absence of ST2 on macrophages was associated with diminished tumor growth.IL-33 promoted polarization of alternatively activated macrophages in an ST2-dependent manner that was mediated via the PI3K/Akt signalling pathway.Moreover,IL-33 inhibited T-cell function by inducing the secretion of transforming growth factorβfrom alternatively activated macrophages.Conclusions:Macrophages expressing ST2 can serve as promising therapeutic targets for NSCLC immunotherapy,highlighting the IL-33/ST2 axis as a potential target for future antitumor strategies.