The highest morbidity and mortality in the world are attributed to digestive system tumors,such as stomach cancer,liver cancer,and pancreatic cancer.Exploring potential biomarkers is a crucial direction of tumor resea...The highest morbidity and mortality in the world are attributed to digestive system tumors,such as stomach cancer,liver cancer,and pancreatic cancer.Exploring potential biomarkers is a crucial direction of tumor research.We use bioinformatics methods to explore potential biomarkers of the digestive system.Mining and analyzing data from Gene Expression Profiling Interactive Analysis(GEPIA),Kaplan-Meier,cBioPortal,and Metabolic gEne RApid Visualizer(MERAV)to explore the correlation between IGF2BP(insulin-like growth factor-2 mRNA-binding protein)family expression and immune infiltration in digestive system tumors,and further probe the prognostic value of IGF2BP family in digestive system tumors.Esophageal cancer tissues showed a significantly higher expression of IGF2BP2 than normal tissues,while IGF2BP3 was notably more expressed in esophageal cancer,pancreatic cancer,and stomach cancer.In the prognosis evaluation,the IGF2BP1 gene in patients with liver cancer and the IGF2BP2 and IGF2BP3 genes in patients with stomach cancer and liver cancer of the low gene expression level groups were better.Multivariate COX regression analysis further suggested that tumor stage,CD8 positive T cells,macrophages,dendritic cell infiltration,and IGF2BP3 expression were independent risk factors affecting the prognosis of patients with stem cell liver cancer.The IGF2BP family may be a potential marker for immunotherapy and the prognosis of digestive system tumors.展开更多
m^(6)A methylation is the most frequent modification of mRNA in eukaryotes and plays a crucial role in cancer progression by regulating biological functions.Insulin-like growth factor 2 mRNA-binding proteins(IGF2BP)ar...m^(6)A methylation is the most frequent modification of mRNA in eukaryotes and plays a crucial role in cancer progression by regulating biological functions.Insulin-like growth factor 2 mRNA-binding proteins(IGF2BP)are newly identified m^(6)A‘readers’.They belong to a family of RNA-binding proteins,which bind to the m^(6)A sites on different RNA sequences and stabilize them to promote cancer progression.In this review,we summarize the mechanisms by which different upstream factors regulate IGF2BP in cancer.The current literature analyzed here reveals that the IGF2BP family proteins promote cancer cell proliferation,survival,and chemoresistance,inhibit apoptosis,and are also associated with cancer glycolysis,angiogenesis,and the immune response in the tumor microenvironment.Therefore,with the discovery of their role as‘readers’of m^(6)A and the characteristic re-expression of IGF2BPs in cancers,it is important to elucidate their mechanism of action in the immunosuppressive tumor microenvironment.We also describe in detail the regulatory and interaction network of the IGF2BP family in downstream target RNAs and discuss their potential clinical applications as diagnostic and prognostic markers,as well as recent advances in IGF2BP biology and associated therapeutic value.展开更多
N6-methyladenosine(m^(6)A)represents the most abundant and functionally significant RNA modification implicated in epigenetic regulation,significantly impacting gene expression through the selective recognition by m^(...N6-methyladenosine(m^(6)A)represents the most abundant and functionally significant RNA modification implicated in epigenetic regulation,significantly impacting gene expression through the selective recognition by m^(6)A reader proteins.Aberrant expression of m^(6)A readers has been associated with cancer progression,contributing to tumor growth,metastasis,drug resistance,and immune evasion.With the increasing research on m^(6)A readers,the discovery of small-molecule inhibitors targeting these proteins has emerged as a promising avenue for cancer therapy.This review delineates the classification and functional roles of m^(6)A readers across various cancers.Furthermore,we summarize and discuss the recent progress in the development of small-molecule inhibitors,with a focus on the medicinal chemistry perspectives.We hope to provide valuable insights to guide future efforts in drug discovery and rational design targeting m^(6)A readers for innovative cancer therapeutics.展开更多
目的:探讨乳酸对三阴性乳腺癌(triple-negative breast cancer,TNBC)细胞恶性行为的影响,并揭示胰岛素样生长因子2 mRNA结合蛋白3(insulin-like growth factor 2 m RNA binding protein 3,IGF2BP3)通过m6A依赖性方式调控EP300,进而介导...目的:探讨乳酸对三阴性乳腺癌(triple-negative breast cancer,TNBC)细胞恶性行为的影响,并揭示胰岛素样生长因子2 mRNA结合蛋白3(insulin-like growth factor 2 m RNA binding protein 3,IGF2BP3)通过m6A依赖性方式调控EP300,进而介导代谢重编程的表观遗传学机制。方法:通过外源性添加乳酸钠处理TNBC细胞,采用CCK-8、集落形成、划痕愈合和Transwell实验检测细胞增殖与迁移能力;利用shRNA慢病毒载体构建IGF2BP3稳定敲低细胞模型,结合Western blot分析组蛋白乳酸化修饰水平;进一步通过RIP-seq、MeRIP-seq筛选IGF2BP3的m6A靶基因,并利用qRT-PCR和Western blot验证关键分子表达。结果:乳酸钠处理显著增强了TNBC细胞的增殖和迁移能力,且泛乳酸化水平随乳酸浓度梯度升高而增加。IGF2BP3敲低可降低组蛋白乳酸化修饰水平。通过整合RIP-seq和MeRIP-seq数据,鉴定出699个其转录本同时被IGF2BP3特异性结合且携带m6A修饰的候选基因,这些基因显著富集于表观遗传调控和代谢相关通路。EP300转录本上IGF2BP3的结合区域与m6A修饰位点高度重合,且EP300的表达水平在IGF2BP3敲低后明显下调。结论:外源性乳酸通过泛乳酸化修饰促进TNBC的恶性进展。IGF2BP3通过m6A依赖性机制调控EP300的表达,进而介导组蛋白乳酸化修饰与代谢重编程的协同作用,最终驱动TNBC的肿瘤进展。上述发现为靶向代谢-表观遗传交互调控的新型治疗策略提供了理论依据。展开更多
基金from any funding agency in the public,commercial,or not-for-profit sectors.
文摘The highest morbidity and mortality in the world are attributed to digestive system tumors,such as stomach cancer,liver cancer,and pancreatic cancer.Exploring potential biomarkers is a crucial direction of tumor research.We use bioinformatics methods to explore potential biomarkers of the digestive system.Mining and analyzing data from Gene Expression Profiling Interactive Analysis(GEPIA),Kaplan-Meier,cBioPortal,and Metabolic gEne RApid Visualizer(MERAV)to explore the correlation between IGF2BP(insulin-like growth factor-2 mRNA-binding protein)family expression and immune infiltration in digestive system tumors,and further probe the prognostic value of IGF2BP family in digestive system tumors.Esophageal cancer tissues showed a significantly higher expression of IGF2BP2 than normal tissues,while IGF2BP3 was notably more expressed in esophageal cancer,pancreatic cancer,and stomach cancer.In the prognosis evaluation,the IGF2BP1 gene in patients with liver cancer and the IGF2BP2 and IGF2BP3 genes in patients with stomach cancer and liver cancer of the low gene expression level groups were better.Multivariate COX regression analysis further suggested that tumor stage,CD8 positive T cells,macrophages,dendritic cell infiltration,and IGF2BP3 expression were independent risk factors affecting the prognosis of patients with stem cell liver cancer.The IGF2BP family may be a potential marker for immunotherapy and the prognosis of digestive system tumors.
基金supported by grants from the Liaoning Nature Science Foundationof China(No.2022JH2/101300042)The National Natural Science Foundation of China(No.82173194,81672877)+1 种基金the Key Research Project of Liaoning Provincial Department of Education of China(No.ZD2020004)2018 Youth Backbone Support Program of China Medical University(No.QGZ2018063).
文摘m^(6)A methylation is the most frequent modification of mRNA in eukaryotes and plays a crucial role in cancer progression by regulating biological functions.Insulin-like growth factor 2 mRNA-binding proteins(IGF2BP)are newly identified m^(6)A‘readers’.They belong to a family of RNA-binding proteins,which bind to the m^(6)A sites on different RNA sequences and stabilize them to promote cancer progression.In this review,we summarize the mechanisms by which different upstream factors regulate IGF2BP in cancer.The current literature analyzed here reveals that the IGF2BP family proteins promote cancer cell proliferation,survival,and chemoresistance,inhibit apoptosis,and are also associated with cancer glycolysis,angiogenesis,and the immune response in the tumor microenvironment.Therefore,with the discovery of their role as‘readers’of m^(6)A and the characteristic re-expression of IGF2BPs in cancers,it is important to elucidate their mechanism of action in the immunosuppressive tumor microenvironment.We also describe in detail the regulatory and interaction network of the IGF2BP family in downstream target RNAs and discuss their potential clinical applications as diagnostic and prognostic markers,as well as recent advances in IGF2BP biology and associated therapeutic value.
基金supported by the National Natural Science Foundation of China(82173680 and 82373741)the Fundamental Research Funds for the Central Universities(2632025TD01,China)+2 种基金the Basic Research Program of Jiangsu for Distinguished Young Scientists(grant BK20220087,China)the China Postdoctoral Science Foundation(2023M743900)the Basic Research Program of Jiangsu(grant BK20241588,China).
文摘N6-methyladenosine(m^(6)A)represents the most abundant and functionally significant RNA modification implicated in epigenetic regulation,significantly impacting gene expression through the selective recognition by m^(6)A reader proteins.Aberrant expression of m^(6)A readers has been associated with cancer progression,contributing to tumor growth,metastasis,drug resistance,and immune evasion.With the increasing research on m^(6)A readers,the discovery of small-molecule inhibitors targeting these proteins has emerged as a promising avenue for cancer therapy.This review delineates the classification and functional roles of m^(6)A readers across various cancers.Furthermore,we summarize and discuss the recent progress in the development of small-molecule inhibitors,with a focus on the medicinal chemistry perspectives.We hope to provide valuable insights to guide future efforts in drug discovery and rational design targeting m^(6)A readers for innovative cancer therapeutics.
文摘目的:探讨乳酸对三阴性乳腺癌(triple-negative breast cancer,TNBC)细胞恶性行为的影响,并揭示胰岛素样生长因子2 mRNA结合蛋白3(insulin-like growth factor 2 m RNA binding protein 3,IGF2BP3)通过m6A依赖性方式调控EP300,进而介导代谢重编程的表观遗传学机制。方法:通过外源性添加乳酸钠处理TNBC细胞,采用CCK-8、集落形成、划痕愈合和Transwell实验检测细胞增殖与迁移能力;利用shRNA慢病毒载体构建IGF2BP3稳定敲低细胞模型,结合Western blot分析组蛋白乳酸化修饰水平;进一步通过RIP-seq、MeRIP-seq筛选IGF2BP3的m6A靶基因,并利用qRT-PCR和Western blot验证关键分子表达。结果:乳酸钠处理显著增强了TNBC细胞的增殖和迁移能力,且泛乳酸化水平随乳酸浓度梯度升高而增加。IGF2BP3敲低可降低组蛋白乳酸化修饰水平。通过整合RIP-seq和MeRIP-seq数据,鉴定出699个其转录本同时被IGF2BP3特异性结合且携带m6A修饰的候选基因,这些基因显著富集于表观遗传调控和代谢相关通路。EP300转录本上IGF2BP3的结合区域与m6A修饰位点高度重合,且EP300的表达水平在IGF2BP3敲低后明显下调。结论:外源性乳酸通过泛乳酸化修饰促进TNBC的恶性进展。IGF2BP3通过m6A依赖性机制调控EP300的表达,进而介导组蛋白乳酸化修饰与代谢重编程的协同作用,最终驱动TNBC的肿瘤进展。上述发现为靶向代谢-表观遗传交互调控的新型治疗策略提供了理论依据。
