Breast cancer is one of the most commonly diagnosed cancers and one of the most significant sources of cancer mortality. Triple negative breast cancer (TNBC) is a particularly aggressive subtype that has proven diffic...Breast cancer is one of the most commonly diagnosed cancers and one of the most significant sources of cancer mortality. Triple negative breast cancer (TNBC) is a particularly aggressive subtype that has proven difficult to treat with standard chemotherapies. Obesity has also been shown to exacerbate breast cancer, and diagnoses of these two diseases frequently overlap. Both conditions are regulated in part by the fat mass and obesity-associated (FTO) demethylase, an RNA demethylase which may drive breast cancers through epigenetic alterations to gene expression. Methods of inhibiting FTO have been researched in vitro and in vivo as an alternative or adjunct to chemotherapies in multiple cancers, including breast cancer. Translating knowledge of the role of FTO in breast cancer and the development of novel agents may allow for improvements in the treatment of this refractory cancer. This review therefore aims to provide an overview of existing and developing chemical inhibitors of FTO that could be innovatively studied for the treatment of TNBC and associated comorbidity.展开更多
Background Non-alcoholic fatty liver disease （NAFLD） is a complex disorder and has been closely linked to obesity.The fat mass and obesity-associated （FTO） gene is a newly discovered gene related to obesity,which ...Background Non-alcoholic fatty liver disease （NAFLD） is a complex disorder and has been closely linked to obesity.The fat mass and obesity-associated （FTO） gene is a newly discovered gene related to obesity,which enhances oxidative stress and tipogenesis in NAFLD.The forkhead transcription factor O1 （FoxO1） is another important gene involved in NAFLD,which causes lipid disorders when insulin resistance appears in the liver.However,the interactions between FTO and FoxO1 during the pathogenesis of NAFLD have not been fully elucidated.This study was designed to identify the relationship between these two factors that are involved in the development of NAFLD.Methods This study includes two parts referred to as animal and cell experiments.Twelve female SPF C57BL/6 mice were fed a high-fat diet to serve as an NAFLD animal model.Aspartate aminotransferase （AST）,alanine aminotransferase （ALT）,total triglyceride （TG）,total cholesterol （TC）,alkaline phosphatase （ALP）,high-density lipoprotein （HDL）,and low-density lipoprotein （LDL） were measured.Immunohistochemical analysis was used to detect the expression and histological localization of FTO,FoxO1,and adenosine monophosphate （AMP）-activated protein kinase （AMPK）.The L02 cells were exposed to high fat for 24,48,or 72 hours.Oil red O staining was used to detect intracellular lipid droplets.Reverse transcription-polymerase chain reaction was used for analyzing the levels of FTO and FoxO1 mRNA.Results At the end of 10 weeks,ALP,ALT,AST,and LDL were significantly increased （P ＜0.01）,while TC and TG were also significantly higher （P ＜0.05）.In addition,HDL was significantly decreased （P ＜0.05）.The FTO and FoxO1 proteins were weakly expressed in the control group,but both FTO and FoxO1 were expressed significantly higher （P ＜0.01） in the experimental group,and the expression of the two factors was significantly correlated.AMPK in the high-fat group showed a low level of correlation with FTO,but not with FoxO1.Oil Red O staining results showed that the cells cultured in 50％ fetal bovine serum for 24,48,or 72 hours exhibited steatosis.FTO and FoxO1 mRNA were increased in the high-fat group compared with the normal group （P ＜0.01）.The expression levels of FTO and FoxO1 mRNA were the highest at 48 hours （P ＜0.05）.Conclusions A high-fat diet leads to higher expression of FTO,phosphorylation of FoxO1,and decreased phosphorylation of AMPK.These results suggest that the interactions between FTO and FoxO1 are closely related to the pathogenesis of NAFLD.展开更多
目的探究脂肪含量和肥胖相关蛋白(fat mass and obesity-associated protein,FTO)和丝氨酸-苏氨酸激酶蛋白激酶D2(serine-threonine kinase protein kinase D2,PRKD2)在糖尿病肾病(diabetic kidney disease,DKD)进展中的调控作用和调节...目的探究脂肪含量和肥胖相关蛋白(fat mass and obesity-associated protein,FTO)和丝氨酸-苏氨酸激酶蛋白激酶D2(serine-threonine kinase protein kinase D2,PRKD2)在糖尿病肾病(diabetic kidney disease,DKD)进展中的调控作用和调节机制。方法采用35 mmol/L葡萄糖对足细胞(MPC5细胞)进行高糖刺激24h构建DKD体外模型。采用FTO过表达载体(pcDNA-FTO)和PRKD2过表达载体(pcDNA-PRKD2),或空载体(vector)转染高糖诱导的MPC5细胞。通过RT-qPCR检测FTO和PRKD2过表达效率;MeRIP检测PRKD2 mRNA的N6-甲基腺苷(N6-methyladenosine,m6A)修饰水平;ELISA检测Caspase-3活性、IL-6,TNF-α和单核细胞趋化蛋白-1(monocyte chemotactic protein-1,MCP-1)分泌量;流式细胞术分析细胞凋亡率;Western blot评估FTO和PRKD2蛋白水平,以及SIRT1/HIF-1α通路关键蛋白表达水平;Pearson分析FTO和PRKD2水平的相关性。结果与无高糖诱导对照组比较,高糖诱导的足细胞中FTO蛋白(0.51±0.04 vs 1.00±0.03)和PRKD2蛋白(0.45±0.03 vs 1.01±0.04)水平显著下调,差异具有统计学意义(t=13.17,16.76,均P<0.001)。高糖诱导的足细胞中FTO蛋白水平和PRKD2蛋白水平呈正相关(r2=0.7051,P<0.001)。与vector组相比,pcDNA-FTO组PRKD2 mRNA的m6A水平(0.56±0.09 vs1.01±0.13)降低,PRKD2 mRNA水平(3.16±0.14 vs 1.03±0.02)显著升高,差异具有统计学意义(t=51.37,11.82,均P<0.001)。与control组(IL-6:512.76±61.85 pg/ml,TNF-α:28.17±2.83 pg/ml,MCP-1:157.31±17.69 pg/ml)和vector组(IL-6:498.41±87.51 pg/ml,TNF-α:26.35±5.47 pg/ml,MCP-1:165.52±16.87 pg/ml)比较,pcDNA-PRKD2组IL-6(301.86±21.85 pg/ml),TNF-α(11.06±4.12 pg/ml),MCP-1分泌量(81.45±9.03pg/ml)显著减少,差异具有统计学意义(F=7.51,10.47,61.97,均P<0.01)。与control组(Caspase-3:689.65±79.5U/L,细胞凋亡率:22.31%±2.69%)和vector组(Caspase-3:715.91±113.58 U/L,细胞凋亡率:21.07%±3.28%)比较,pcDNA-PRKD2组Caspase-3活性(437.64±104.76 U/L)和细胞凋亡率(8.41%±3.15%)下降,差异具有统计学意义(F=2.35,79.13,均P<0.01)。与control组(SIRT1:1.01±0.05,HIF-1α:1.03±0.07)和vector组(SIRT1:0.97±0.05,HIF-1α:1.02±0.03)相比,pcDNA-PRKD2组SIRT1蛋白(3.51±0.15)水平升高,HIF-1α蛋白(0.37±0.07)水平降低,差异具有统计学意义(F=31.54,8.31,均P<0.01)。结论FTO介导m6A修饰的PRKD2通过SIRT1/HIF-1α通路抑制高糖诱导的足细胞炎症反应和细胞凋亡。展开更多
目的探讨邻苯二甲酸二(2-乙基己基)酯(di-2-ethylhexyl phthalate,DEHP)诱导睾丸间质细胞铁死亡中RNA去甲基化酶脂肪量和肥胖相关蛋白(fat mass and obesity-associated protein,FTO)的作用及机制。方法40只3周龄C57BL/6雄性小鼠通过随...目的探讨邻苯二甲酸二(2-乙基己基)酯(di-2-ethylhexyl phthalate,DEHP)诱导睾丸间质细胞铁死亡中RNA去甲基化酶脂肪量和肥胖相关蛋白(fat mass and obesity-associated protein,FTO)的作用及机制。方法40只3周龄C57BL/6雄性小鼠通过随机数字表法分为对照组(玉米油)和3组DEHP染毒组(5、250、500 mg/kg体质量),连续灌胃35 d;TM3小鼠睾丸间质细胞以0、100、200、400μmol/L邻苯二甲酸单(2-乙基己基)酯(mono-2-ethylhexyl phthalate,MEHP)处理24 h,质粒转染构建Fto过表达TM3细胞。ELISA检测血清睾酮水平,免疫组化检测睾丸组织中蛋白表达,比色法检测睾丸中Fe 2+、丙二醛和脂质过氧化物水平。甲基化RNA免疫共沉淀、RT-PCR和Western blot检测N6-甲基腺嘌呤(N6-methyladenosine,m6A)修饰水平。结果250、500 mg/kg DEHP染毒组小鼠的血清睾酮水平显著降低(P<0.01),睾丸组织Fe 2+、丙二醛、脂质过氧化物水平显著升高(P<0.01),RNA去甲基化酶FTO、铁死亡相关分子铁蛋白重链1(ferritin heavy chain 1,FTH1)和谷胱甘肽过氧化酶4(glutathione peroxidase 4,GPX4)蛋白水平显著下调(P<0.05),转铁蛋白受体(transferrin receptor,TFRC)、膜铁转运蛋白(ferroportin,FPN)、环氧合酶-2(cyclooxygenase-2,COX-2)和酰基辅酶A合成酶长链家族成员4(acyl-CoA synthetase long-chain family member 4,ACSL4)蛋白水平显著上调(P<0.05)。MEHP处理TM3细胞24 h后,细胞活力下降、胞内活性氧(ROS)含量升高,线粒体膜电位(mitochondrial membrane potential,MMP)显著降低(P<0.01),Fto的mRNA和蛋白水平均显著下调(P<0.01),其余铁死亡相关蛋白的变化也与睾丸组织中趋势一致,提示睾丸间质细胞发生了铁死亡。以铁死亡抑制剂Fer-1干预或过表达Fto均能显著抑制MEHP诱导的TM3细胞毒性和铁死亡(P<0.05),同时过表达Fto使Gpx4和Fth1 mRNA的m6A修饰水平降低(P<0.05)。结论FTO表达抑制引起Gpx4、Fth1的m6A修饰异常可能是DEHP诱导睾丸间质细胞铁死亡的机制。展开更多
胃癌是消化系统最常见的恶性肿瘤之一,多数患者发现时已处于晚期,预后不佳。外科手术及化学治疗(化疗仍是目前胃癌的主要治疗方式。N6-甲基腺嘌呤(N6-methyladenosine,m^(6)A)是近年来肿瘤研究的热点。m^(6)A作为真核生物中最常见的RNA...胃癌是消化系统最常见的恶性肿瘤之一,多数患者发现时已处于晚期,预后不佳。外科手术及化学治疗(化疗仍是目前胃癌的主要治疗方式。N6-甲基腺嘌呤(N6-methyladenosine,m^(6)A)是近年来肿瘤研究的热点。m^(6)A作为真核生物中最常见的RNA修饰形式,可以调控RNA循环的各个阶段,包括RNA剪接、加工、降解和翻译等,从而调控RNA的表达和功能,在细胞分化、发育和代谢等各个环节中发挥关键作用。m^(6)A去甲基化酶可去除RNA上的甲基基团,确保m^(6)A甲基化是一个动态的可逆的过程。作为m^(6)A甲基化过程的关键酶,m^(6)A去甲基化酶——脂肪和肥胖相关蛋白(fat mass and obesity-associated protein,FTO)、AlkB同系物5(AlkB homolog 5,ALKBH5)、ALKBH3的失调能通过多种机制调控胃癌的演进过程,与胃癌的发生发展密切相关。m^(6)A去甲基化酶通过调节信号通路,改变胃癌细胞的增殖和侵袭能力,影响胃癌对化疗药物的耐药性,参与调控胃癌的免疫应答及线粒体代谢,从而影响胃癌细胞的生长,有望成为一个全新的治疗靶点。该文综述了m^(6)A去甲基化酶参与胃癌发生发展的分子机制,以及其表达和功能与胃癌生物学特性的关系,旨在为胃癌的早期诊断和靶向治疗提供新的研究思路。展开更多
N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)是RNA最常见的内部修饰,在RNA的加工、转运、翻译及稳定性方面发挥重要作用。脂肪量和肥胖相关基因(fat mass and obesity-associated,FTO)作为第一个被发现的mRNA m^(6)A去甲基化酶,参与...N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)是RNA最常见的内部修饰,在RNA的加工、转运、翻译及稳定性方面发挥重要作用。脂肪量和肥胖相关基因(fat mass and obesity-associated,FTO)作为第一个被发现的mRNA m^(6)A去甲基化酶,参与多种肿瘤的发生、发展及治疗抵抗,调节肿瘤干细胞自我更新、肿瘤代谢及肿瘤微环境。作为肿瘤治疗有希望的靶点,越来越多的FTO抑制剂被研发出来并在临床前研究中取得了良好的治疗效果。本研究就FTO在肿瘤发生、肿瘤干细胞自我更新、肿瘤免疫和代谢及治疗抵抗等方面的功能和潜在分子机制的研究进展作一综述,并讨论靶向FTO在肿瘤治疗中的应用前景。展开更多
文摘Breast cancer is one of the most commonly diagnosed cancers and one of the most significant sources of cancer mortality. Triple negative breast cancer (TNBC) is a particularly aggressive subtype that has proven difficult to treat with standard chemotherapies. Obesity has also been shown to exacerbate breast cancer, and diagnoses of these two diseases frequently overlap. Both conditions are regulated in part by the fat mass and obesity-associated (FTO) demethylase, an RNA demethylase which may drive breast cancers through epigenetic alterations to gene expression. Methods of inhibiting FTO have been researched in vitro and in vivo as an alternative or adjunct to chemotherapies in multiple cancers, including breast cancer. Translating knowledge of the role of FTO in breast cancer and the development of novel agents may allow for improvements in the treatment of this refractory cancer. This review therefore aims to provide an overview of existing and developing chemical inhibitors of FTO that could be innovatively studied for the treatment of TNBC and associated comorbidity.
文摘Background Non-alcoholic fatty liver disease （NAFLD） is a complex disorder and has been closely linked to obesity.The fat mass and obesity-associated （FTO） gene is a newly discovered gene related to obesity,which enhances oxidative stress and tipogenesis in NAFLD.The forkhead transcription factor O1 （FoxO1） is another important gene involved in NAFLD,which causes lipid disorders when insulin resistance appears in the liver.However,the interactions between FTO and FoxO1 during the pathogenesis of NAFLD have not been fully elucidated.This study was designed to identify the relationship between these two factors that are involved in the development of NAFLD.Methods This study includes two parts referred to as animal and cell experiments.Twelve female SPF C57BL/6 mice were fed a high-fat diet to serve as an NAFLD animal model.Aspartate aminotransferase （AST）,alanine aminotransferase （ALT）,total triglyceride （TG）,total cholesterol （TC）,alkaline phosphatase （ALP）,high-density lipoprotein （HDL）,and low-density lipoprotein （LDL） were measured.Immunohistochemical analysis was used to detect the expression and histological localization of FTO,FoxO1,and adenosine monophosphate （AMP）-activated protein kinase （AMPK）.The L02 cells were exposed to high fat for 24,48,or 72 hours.Oil red O staining was used to detect intracellular lipid droplets.Reverse transcription-polymerase chain reaction was used for analyzing the levels of FTO and FoxO1 mRNA.Results At the end of 10 weeks,ALP,ALT,AST,and LDL were significantly increased （P ＜0.01）,while TC and TG were also significantly higher （P ＜0.05）.In addition,HDL was significantly decreased （P ＜0.05）.The FTO and FoxO1 proteins were weakly expressed in the control group,but both FTO and FoxO1 were expressed significantly higher （P ＜0.01） in the experimental group,and the expression of the two factors was significantly correlated.AMPK in the high-fat group showed a low level of correlation with FTO,but not with FoxO1.Oil Red O staining results showed that the cells cultured in 50％ fetal bovine serum for 24,48,or 72 hours exhibited steatosis.FTO and FoxO1 mRNA were increased in the high-fat group compared with the normal group （P ＜0.01）.The expression levels of FTO and FoxO1 mRNA were the highest at 48 hours （P ＜0.05）.Conclusions A high-fat diet leads to higher expression of FTO,phosphorylation of FoxO1,and decreased phosphorylation of AMPK.These results suggest that the interactions between FTO and FoxO1 are closely related to the pathogenesis of NAFLD.
文摘胃癌是消化系统最常见的恶性肿瘤之一,多数患者发现时已处于晚期,预后不佳。外科手术及化学治疗(化疗仍是目前胃癌的主要治疗方式。N6-甲基腺嘌呤(N6-methyladenosine,m^(6)A)是近年来肿瘤研究的热点。m^(6)A作为真核生物中最常见的RNA修饰形式,可以调控RNA循环的各个阶段,包括RNA剪接、加工、降解和翻译等,从而调控RNA的表达和功能,在细胞分化、发育和代谢等各个环节中发挥关键作用。m^(6)A去甲基化酶可去除RNA上的甲基基团,确保m^(6)A甲基化是一个动态的可逆的过程。作为m^(6)A甲基化过程的关键酶,m^(6)A去甲基化酶——脂肪和肥胖相关蛋白(fat mass and obesity-associated protein,FTO)、AlkB同系物5(AlkB homolog 5,ALKBH5)、ALKBH3的失调能通过多种机制调控胃癌的演进过程,与胃癌的发生发展密切相关。m^(6)A去甲基化酶通过调节信号通路,改变胃癌细胞的增殖和侵袭能力,影响胃癌对化疗药物的耐药性,参与调控胃癌的免疫应答及线粒体代谢,从而影响胃癌细胞的生长,有望成为一个全新的治疗靶点。该文综述了m^(6)A去甲基化酶参与胃癌发生发展的分子机制,以及其表达和功能与胃癌生物学特性的关系,旨在为胃癌的早期诊断和靶向治疗提供新的研究思路。
文摘N^(6)-甲基腺苷(N^(6)-methyladenosine,m^(6)A)是RNA最常见的内部修饰,在RNA的加工、转运、翻译及稳定性方面发挥重要作用。脂肪量和肥胖相关基因(fat mass and obesity-associated,FTO)作为第一个被发现的mRNA m^(6)A去甲基化酶,参与多种肿瘤的发生、发展及治疗抵抗,调节肿瘤干细胞自我更新、肿瘤代谢及肿瘤微环境。作为肿瘤治疗有希望的靶点,越来越多的FTO抑制剂被研发出来并在临床前研究中取得了良好的治疗效果。本研究就FTO在肿瘤发生、肿瘤干细胞自我更新、肿瘤免疫和代谢及治疗抵抗等方面的功能和潜在分子机制的研究进展作一综述,并讨论靶向FTO在肿瘤治疗中的应用前景。
