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: Obesity is a common public health issue and is currently deemed a disease. Research has shown that the risk of gallstones in individuals with obesity is elevated. This study aimed to explore the bile prote...Background: Obesity is a common public health issue and is currently deemed a disease. Research has shown that the risk of gallstones in individuals with obesity is elevated. This study aimed to explore the bile proteomics differences between cholelithiasis patients with obesity and normal body weight. Methods: Bile samples from 20 patients(10 with obesity and 10 with normal body weight) who underwent laparoscopic cholecystectomy at our center were subjected to tandem mass tag labeling(TMT) and liquid chromatography-tandem mass spectrometry(LC-MS/MS), followed by further bioinformatic analysis. Results: Among the differentially expressed proteins, 23 were upregulated and 67 were downregulated. Bioinformatic analysis indicated that these differentially expressed proteins were mainly involved in cell development, inflammatory responses, glycerolipid metabolic processes, and protein activation cascades. In addition, the activity of the peroxisome proliferator-activated receptor(PPAR, a subfamily of nuclear receptors) signaling pathway was decreased in the Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis. Two downregulated proteins in the PPAR signaling pathway, APO A-Ⅰ and APO A-Ⅱ, were confirmed using enzyme-linked immunosorbent assay. Conclusions: The PPAR signaling pathway may play a crucial role in the development of cholelithiasis among patients with obesity. Furthermore, biliary proteomics profiling of gallstones patients with obesity is revealed, providing a reference for future research.展开更多
BACKGROUND Through experimental research on the biological function of GATA6-AS1,it was confirmed that GATA6-AS1 can inhibit the proliferation,invasion,and migration of gastric cancer cells,suggesting that GATA6-AS1 p...BACKGROUND Through experimental research on the biological function of GATA6-AS1,it was confirmed that GATA6-AS1 can inhibit the proliferation,invasion,and migration of gastric cancer cells,suggesting that GATA6-AS1 plays a role as an anti-oncogene in the occurrence and development of gastric cancer.Further experi-ments confirmed that the overexpression of fat mass and obesity-associated protein(FTO)inhibited the expression of GATA6-AS1,thereby promoting the occurrence and development of gastric cancer.AIM To investigate the effects of GATA6-AS1 on the proliferation,invasion and migration of gastric cancer cells and its mechanism of action.METHODS We used bioinformatics methods to analyze the Cancer Genome Atlas(https://portal.gdc.cancer.gov/.The Cancer Genome Atlas)and download expression data for GATA6-AS1 in gastric cancer tissue and normal tissue.We also constructed a GATA6-AS1 lentivirus overexpression vector which was transfected into gastric cancer cells to investigate its effects on proliferation,migration and invasion,and thereby clarify the expression of GATA6-AS1 in gastric cancer and its biological role in the genesis and development of gastric cancer.Next,we used a database(http://starbase.sysu.edu.cn/starbase2/)to analysis GATA6-AS1 whether by m6A methylation modify regulation and predict the methyltransferases that may methylate GATA6-AS1.Furthermore,RNA immunoprecipitation experiments confirmed that GATA6-AS1 was able to bind to the m6A methylation modification enzyme.These data allowed us to clarify the ability of m6A methylase to influence the action of GATA6-AS1 and its role in the occurrence and development of gastric cancer.RESULTS Low expression levels of GATA6-AS1 were detected in gastric cancer.We also determined the effects of GATA6-AS1 overexpression on the biological function of gastric cancer cells.GATA6-AS1 had strong binding ability with the m6A demethylase FTO,which was expressed at high levels in gastric cancer and negatively correlated with the expression of GATA6-AS1.Following tr展开更多
Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies （GWAS） has ha...Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies （GWAS） has hastened the progress of polygenic obesity research. As of this writing, more than 73 obesity susceptibility loci have been identified in ethnic groups through GWAS. The identified loci explain only 2% to 4% of obesity heritability, thereby indicating that a large proportion of loci remain undiscovered. Thus, the next step is to identify and confirm novel loci, which may exhibit smaller effects and lower allele frequencies than established loci. However, achieving these tasks has been difficult for researchers. GWAS help researchers discover the causal loci. Moreover, numerous biological studies have been performed on the polygenic effects on obesity, such as studies on fat mass- and obesity-associated gene （FTO）, but the role of these polygenic effects in the mechanism of obesity remains unclear. Thus, obesity-causing variations should be identified, and insights into the biology of polygenic effects on obesity are needed.展开更多
Background:The hypocaloric diets improve glycemic status in obese individuals,but the response to hypocaloric diets in fat mass and obesity-associated gene(FTO)-rs9939609 gene variant is unknown.This systematic review...Background:The hypocaloric diets improve glycemic status in obese individuals,but the response to hypocaloric diets in fat mass and obesity-associated gene(FTO)-rs9939609 gene variant is unknown.This systematic review and meta-analysis aimed to assess the gene-diet interaction of FTO-rs9939609 gene variant and hypocaloric diets on glycemic control in overweight and obese adults.Methods:Cochrane Central Register of Controlled Trials,PubMed,ISI Web of Science,Embase,Scopus,and Google scholar were searched up to December 2018,for relevant clinical trials.Mean changes in fasting blood sugar(FBS),serum insulin,and homeostasis model assessment of insulin resistance(HOMA-IR)were extracted.Results:The pooled analysis of nine studies showed that there was no significant difference between AA/AT and TT genotypes in FBS(weighted mean difference[WMD]=0.01,95%confidence interval[CI]:-1.08,1.10,P=0.984)and serum insulin(WMD=0.20,95%CI:-0.85,1.26;P=0.707)after intervention hypocaloric diets.The overweight/obese participants in AA/AT group showed the greatest reduction in HOMA-IR compared with TT genotype following intervention,and this difference was not statistically significant(WMD=-0.38,95%CI:-0.94,0.16,P=0.167).Conclusion:This meta-analysis suggests that there was no significant difference between AA/AT and TT genotypes of FTO-rs9939609 on FBS,serum insulin level,and insulin resistance in response to hypocaloric diets.展开更多
Uveitis,a vision-threatening inflammatory disease worldwide,is closely related to resident microglia.Retinal microglia are the main immune effector cells with strong plasticity,but their role in uveitis remains unclea...Uveitis,a vision-threatening inflammatory disease worldwide,is closely related to resident microglia.Retinal microglia are the main immune effector cells with strong plasticity,but their role in uveitis remains unclear.N6-methyladenosine(m^(6)A)modification has been proven to be involved in the immune response.Therefore,we in this work aimed to identify the potentially crucial m^(6)A regulators of microglia in uveitis.Through the single-cell sequencing(scRNA-seq)analysis and experimental verification,we found a significant decrease in the expression of fat mass and obesity-associated protein(FTO)in retinal microglia of uveitis mice and human microglia clone 3(HMC3)cells with inflammation.Additionally,FTO knockdown was found to aggravate the secretion of inflammatory factors and the mobility/chemotaxis of microglia.Mechanistically,the RNA-seq data and rescue experiments showed that glypican 4(GPC4)was the target of FTO,which regulated microglial inflammation mediated by the TLR4/NF-κB pathway.Moreover,RNA stability assays indicated that GPC4 upregulation was mainly regulated by the downregulation of the m^(6)A“reader”YTH domain family protein 3(YTHDF3).Finally,the FTO inhibitor FB23-2 further exacerbated experimental autoimmune uveitis(EAU)inflammation by promoting the GPC4/TLR4/NF-κB signaling axis,and this could be attenuated by the TLR4 inhibitor TAK-242.Collectively,a decreased FTO could facilitate microglial inflammation in EAU,suggesting that the restoration or activation of FTO function may be a potential therapeutic strategy for uveitis.展开更多
背景与目的近年来,研究已证实在包括乳腺癌在内的多种肿瘤的进展中,RNA的N6-甲基腺苷(N6-methyladenosine,m^(6)A)修饰是一个重要的调节过程。脂肪量与肥胖相关(fat mass and obesityassociated,FTO)酶,最初被称为肥胖相关蛋白,是第一...背景与目的近年来,研究已证实在包括乳腺癌在内的多种肿瘤的进展中,RNA的N6-甲基腺苷(N6-methyladenosine,m^(6)A)修饰是一个重要的调节过程。脂肪量与肥胖相关(fat mass and obesityassociated,FTO)酶,最初被称为肥胖相关蛋白,是第一个被发现的m^(6)A去甲基化酶。然而,FTO与乳腺癌之间的关系目前还存在争议。本研究旨在阐明FTO在乳腺癌中的作用及其临床意义,并探讨其作用机制。方法我们首先用定量逆转录–PCR(quantitative reverse transcription-PCR,qRT-PCR)、Western blotting和免疫组织化学法检测了乳腺癌细胞系和组织中FTO的表达。用划痕实验和Transwell实验检测了FTO过表达或表达敲降的SKBR3和MDA-MB453细胞的迁移和侵袭能力。采用RNA测序(RNA sequencing,RNA-seq)分析FTO的下游靶分子。采用qRT-PCR、荧光素酶报告基因分析和Western blotting证实FTO/miR-181b-p/ARL5B轴。用划痕实验和Transwell侵袭实验检测了ADP核糖基化因子样蛋白GTP酶5B(ADP ribosylation factor like GTPase 5B,ARL5B)在乳腺癌细胞中的生物学功能。结果人表皮生长因子受体2(human epidermal growth factor receptor 2,HER2)表达阳性的乳腺癌中FTO高表达,其高表达与肿瘤进展[肿瘤大小(P<0.001)、核分级(P=0.001)、癌旁淋巴及血管浸润(P<0.001)、淋巴结转移(P=0.002)及TNM分期(P=0.001)]及不良预后相关。另外,体外实验证实FTO可增强乳腺癌细胞的迁移及侵袭。在机制方面,RNA测序和进一步的验证实验均表明,FTO可通过抑制miR-181b-3p上调ARL5B的表达。我们进一步证实了ARL5B在乳腺癌细胞中发挥了致癌活性。结论本研究证实了FTO可通过FTO/miR181b-3p/ARL5B通路促进乳腺癌细胞的迁移及侵袭。展开更多
This study explored how bitter melon powder （BMP） alters the colonic microenvironment during the development of obesity-associated fatty liver in rats. We observed that BMP effectively inhibited the body weight gain...This study explored how bitter melon powder （BMP） alters the colonic microenvironment during the development of obesity-associated fatty liver in rats. We observed that BMP effectively inhibited the body weight gain and lipid accumulation in the liver, ameliorated glucose intolerance, and increased the colon weight after an 8-week treatment compared to that in the high-fat diet （HFD） group. BMP significantly decreased fecal water toxicity towards HT-29 cells, as revealed by the cell counting kit （CCK）-8 assay results, and the mRNA expression of Toll-like receptor 4 （TLR4） in colon mucosa. Additionally, gut permeability in the BMP group was restored to normal levels. Finally, BMP alleviated the inflammatory state of the rat colon mucosa and liver tissues as well as the systemic inflammation.展开更多
N6-methyladenosine(m6A)modification is the most widespread and conserved internal mRNA modification in mammalian cells.It greatly affects genetic regulation by enhancing the involvement of diverse cellular enzymes and...N6-methyladenosine(m6A)modification is the most widespread and conserved internal mRNA modification in mammalian cells.It greatly affects genetic regulation by enhancing the involvement of diverse cellular enzymes and thus,plays a significant role in basic life processes.Numerous studies on m6A modification identified FTO as a crucial demethylase that participates in various biological processes.Not only does FTO play a pivotal role in obesity-related conditions,but it also influences the occurrence,development,and prognosis of several cancers,such as acute myeloid leukemia,breast cancer,liver cancer,and lung cancer.Moreover,FTO also shows a close association with immunity and viral infections.This article summarized the molecular mechanism of FTO in tumorigenesis and tumor progression.展开更多
Background:N6-methyladenosine(m6A)RNA modification has been demonstrated to be a significant regulatory process in the progression of various tumors,including breast cancer.Fat mass and obesity-associated(FTO)enzyme,i...Background:N6-methyladenosine(m6A)RNA modification has been demonstrated to be a significant regulatory process in the progression of various tumors,including breast cancer.Fat mass and obesity-associated(FTO)enzyme,initially known as the obesity-related protein,is the first identified m6A demethylase.However,the relationship between FTO and breast cancer remains controversial.In this study,we aimed to elucidate the role and clinical significance of FTO in breast cancer and to explore the underlying mechanism.Methods:We first investigated the expression of FTO in breast cancer cell lines and tissues by quantitative reverse transcription-PCR(qRT-PCR),Western blotting,and immunohistochemistry.Wound healing assay and Transwell assay were performed to determine the migration and invasion abilities of SKBR3 and MDAMB453 cells with either knockdown or overexpression of FTO.RNA sequencing(RNA-seq)was conducted to decipher the downstream targets of FTO.qRT-PCR,luciferase reporter assay,and Western blotting were employed to confirm the existence of the FTO/miR-181b-3p/ARL5B axis.The biological function of ADP ribosylation factor like GTPase 5B(ARL5B)in breast cancer cells was evaluated by wound healing assay and Transwell invasion assay.Results:High FTO expression was observed in human epidermal growth factor receptor 2(HER2)-positive breast cancer,predicting advanced progression(tumor size[P<0.001],nuclear grade[P=0.001],peritumoral lymphovascular invasion[P<0.001),lymph node metastasis[P=0.002],and TNM stage[P=0.001])and poor prognosis.Moreover,FTO promoted cell invasion and migration in vitro.Mechanistically,RNA-seq and further confirmation studies suggested that FTO up-regulated ARL5B by inhibiting miR-181b-3p.We further verified that ARL5B also displayed carcinogenic activity in breast cancer cells.Conclusion:Our work demonstrated the carcinogenic activity of FTO in promoting the invasion and migration of breast cancer cells via the FTO/miR-181b-3p/ARL5B signaling pathway.展开更多
目的研究FTO(fat-mass and obesity associated)基因SNP rs9939609和rs1421085多态性与儿童青少年单纯性肥胖及其代谢指标的相关性。方法以2004至2006年于复旦大学附属儿科医院内分泌门诊就诊的汉族单纯性肥胖和超重儿童青少年分别作为...目的研究FTO(fat-mass and obesity associated)基因SNP rs9939609和rs1421085多态性与儿童青少年单纯性肥胖及其代谢指标的相关性。方法以2004至2006年于复旦大学附属儿科医院内分泌门诊就诊的汉族单纯性肥胖和超重儿童青少年分别作为肥胖组和超重组;选择上海市某中学正常体重汉族学生作为正常对照组。分别测量身高和体重,计算BMI。测定血清空腹葡萄糖(FPG)、空腹胰岛素(FIns)、三酰甘油(TG)和总胆固醇(TC)水平。计算胰岛素抵抗指数(HOMA-IR)和胰岛素敏感指数(QUICKI)。抽提外周血基因组DNA,采用Taqman-MGB探针技术检测FTO基因SNPrs9939609和rs1421085多态性,分析不同基因型与代谢指标和BMI的相关性。结果肥胖组纳入236例,超重组纳入239例,正常对照组纳入241名。肥胖+超重组的BMI、FPG、FIns、TG和HOMA-IR显著高于正常对照组;②肥胖、超重和正常对照组rs9939609分型成功率分别为94.9%(224/236例)、97.9(234/239例)和95.9%(231/241名),rs1421085分型成功率分别为92.8%(219/236例)、97.1%(232/239例)和95.4%(230/241名)。rs9939609AA基因型频率:肥胖组为2.7%,超重组为0.4%,正常对照组为1.7%,肥胖+超重组A等位基因频率显著高于正常对照组(OR=1.437,P=0.048);rs1421085CC基因型频率:肥胖组为2.7%,超重组为0.9%,正常对照组为1.7%,肥胖+超重组C等位基因频率高于正常对照组,但差异无统计学意义(OR=1.388,P=0.0760);③rs1421085TC+CC基因型和rs9939609TA+AA基因型儿童青少年的BMI显著高于TT基因型(rs9939609:P=0.0003;rs1421085:P=0.0005);rs1421085TC+CC基因型和rs9939609TA+AA基因型与FPG、FIns、TG、TC、HOMA-IR、QUICKI无显著相关性。结论FTO基因SNP rs9939609和rs1421085多态性与中国汉族儿童青少年肥胖和(或)超重存在相关性。A等位基因频率远低于欧洲人群,对BMI的作用效果与欧洲人群相似,但对代谢指标影响存在显著差异。展开更多
肥胖相关蛋白(fat mass and obesity-associated protein,FTO)是一种位于染色体16q12.2上的N6-甲基腺苷(m^6A)去甲基酶,以往的研究证实FTO可通过3’非翻译区域调节下游的m^6A水平来影响肥胖。随着研究的不断深入,研究者们发现,m^6A甲基...肥胖相关蛋白(fat mass and obesity-associated protein,FTO)是一种位于染色体16q12.2上的N6-甲基腺苷(m^6A)去甲基酶,以往的研究证实FTO可通过3’非翻译区域调节下游的m^6A水平来影响肥胖。随着研究的不断深入,研究者们发现,m^6A甲基化这一表观遗传修饰能通过调控肿瘤基因、抑肿瘤基因的mRNA分子的表达水平调控肿瘤的发生发展。FTO作为m^6A修饰的重要组成部分,参与调控多种肿瘤的发生、发展及其预后。目前研究表明,FTO能够通过不同方式(影响肿瘤细胞生长和增殖、抑制细胞分化、干预肿瘤干细胞自我更新、影响肿瘤转移和放化疗敏感性等)参与调控多种肿瘤发生发展。因此,FTO有望在不久的将来成为诊断和治疗肿瘤的新靶点,特别是针对某些特定类型的肿瘤,如急性髓系白血病、胶质母细胞癌和乳腺癌等,这对于肿瘤的诊疗具有重要的理论意义和应用价值。本文拟通过对目前有关FTO的研究进行整理和分析,对FTO在肿瘤中的作用及其研究进展进行了综述。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展开更多
目的评价脂肪量与肥胖相关基因(fat mass and obesity-associated gene,FTO)的多个单核苷酸多态性位点(single nucleotide polymorphisms,SNP)与乳腺癌发病的相关性。方法全面检索Pubmed、Embase、Web of science、中国知网(CNKI)、万...目的评价脂肪量与肥胖相关基因(fat mass and obesity-associated gene,FTO)的多个单核苷酸多态性位点(single nucleotide polymorphisms,SNP)与乳腺癌发病的相关性。方法全面检索Pubmed、Embase、Web of science、中国知网(CNKI)、万方数据库及中国生物医学文献数据库(CBM),获取11个FTO基因多态性与乳腺癌易感性的病例-对照研究,对不同SNP位点采用等位基因位点、共显性遗传模型、显性遗传模型、隐性遗传模型分别评价乳腺癌发病的相对危险度,并对异质性较大的遗传模型,进行不同人种的亚组分析。运用Meta分析方法综合评价FTO的SNP位点(rs9939609、rs1477196、rs1121980)与乳腺癌的相关性。结果共有6篇病例-对照研究文献被纳入,包括2994例乳腺癌患者和3699名健康对照,Meta分析结果显示:rs1477196基因多态性在显性遗传模型中与乳腺癌具有相关性(OR=1.241,95%CI为1.035~1.488,P=0.019);rs9939609和rs1121980基因多态性与乳腺癌均无明显相关性(OR=1.062,95%CI为0.934~1.208,P=0.36)。人种亚组分析则显示rs1477196的G等位基因在亚洲人中与乳腺癌显著相关(OR=1.305,95%CI为1.085~1.569,P=0.005),但与高加索人(OR=1.136,95%CI为0.641~2.014,P=0.662)和混合人种(OR=1.131,95%CI为0.809~1.583,P=0.472)均无相关性。结论 FTO多态性与乳腺癌的易感性在不同遗传模型及人种中有差异。亚洲人中rs1477196的G等位基因与乳腺癌发病呈正相关。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.
基金Public Welfare Re-search Fund of Huzhou City(2018GYB60).
文摘Background: Obesity is a common public health issue and is currently deemed a disease. Research has shown that the risk of gallstones in individuals with obesity is elevated. This study aimed to explore the bile proteomics differences between cholelithiasis patients with obesity and normal body weight. Methods: Bile samples from 20 patients(10 with obesity and 10 with normal body weight) who underwent laparoscopic cholecystectomy at our center were subjected to tandem mass tag labeling(TMT) and liquid chromatography-tandem mass spectrometry(LC-MS/MS), followed by further bioinformatic analysis. Results: Among the differentially expressed proteins, 23 were upregulated and 67 were downregulated. Bioinformatic analysis indicated that these differentially expressed proteins were mainly involved in cell development, inflammatory responses, glycerolipid metabolic processes, and protein activation cascades. In addition, the activity of the peroxisome proliferator-activated receptor(PPAR, a subfamily of nuclear receptors) signaling pathway was decreased in the Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment analysis. Two downregulated proteins in the PPAR signaling pathway, APO A-Ⅰ and APO A-Ⅱ, were confirmed using enzyme-linked immunosorbent assay. Conclusions: The PPAR signaling pathway may play a crucial role in the development of cholelithiasis among patients with obesity. Furthermore, biliary proteomics profiling of gallstones patients with obesity is revealed, providing a reference for future research.
基金Natural Science Foundation of Shandong Province,No.ZR2020MH207 and No.ZR2020MH251.
文摘BACKGROUND Through experimental research on the biological function of GATA6-AS1,it was confirmed that GATA6-AS1 can inhibit the proliferation,invasion,and migration of gastric cancer cells,suggesting that GATA6-AS1 plays a role as an anti-oncogene in the occurrence and development of gastric cancer.Further experi-ments confirmed that the overexpression of fat mass and obesity-associated protein(FTO)inhibited the expression of GATA6-AS1,thereby promoting the occurrence and development of gastric cancer.AIM To investigate the effects of GATA6-AS1 on the proliferation,invasion and migration of gastric cancer cells and its mechanism of action.METHODS We used bioinformatics methods to analyze the Cancer Genome Atlas(https://portal.gdc.cancer.gov/.The Cancer Genome Atlas)and download expression data for GATA6-AS1 in gastric cancer tissue and normal tissue.We also constructed a GATA6-AS1 lentivirus overexpression vector which was transfected into gastric cancer cells to investigate its effects on proliferation,migration and invasion,and thereby clarify the expression of GATA6-AS1 in gastric cancer and its biological role in the genesis and development of gastric cancer.Next,we used a database(http://starbase.sysu.edu.cn/starbase2/)to analysis GATA6-AS1 whether by m6A methylation modify regulation and predict the methyltransferases that may methylate GATA6-AS1.Furthermore,RNA immunoprecipitation experiments confirmed that GATA6-AS1 was able to bind to the m6A methylation modification enzyme.These data allowed us to clarify the ability of m6A methylase to influence the action of GATA6-AS1 and its role in the occurrence and development of gastric cancer.RESULTS Low expression levels of GATA6-AS1 were detected in gastric cancer.We also determined the effects of GATA6-AS1 overexpression on the biological function of gastric cancer cells.GATA6-AS1 had strong binding ability with the m6A demethylase FTO,which was expressed at high levels in gastric cancer and negatively correlated with the expression of GATA6-AS1.Following tr
文摘Obesity prevalence has increased in recent years. Lifestyle change fuels obesity, but genetic factors cause more than 50% of average variations in obesity. The advent of genome-wide association studies （GWAS） has hastened the progress of polygenic obesity research. As of this writing, more than 73 obesity susceptibility loci have been identified in ethnic groups through GWAS. The identified loci explain only 2% to 4% of obesity heritability, thereby indicating that a large proportion of loci remain undiscovered. Thus, the next step is to identify and confirm novel loci, which may exhibit smaller effects and lower allele frequencies than established loci. However, achieving these tasks has been difficult for researchers. GWAS help researchers discover the causal loci. Moreover, numerous biological studies have been performed on the polygenic effects on obesity, such as studies on fat mass- and obesity-associated gene （FTO）, but the role of these polygenic effects in the mechanism of obesity remains unclear. Thus, obesity-causing variations should be identified, and insights into the biology of polygenic effects on obesity are needed.
文摘Background:The hypocaloric diets improve glycemic status in obese individuals,but the response to hypocaloric diets in fat mass and obesity-associated gene(FTO)-rs9939609 gene variant is unknown.This systematic review and meta-analysis aimed to assess the gene-diet interaction of FTO-rs9939609 gene variant and hypocaloric diets on glycemic control in overweight and obese adults.Methods:Cochrane Central Register of Controlled Trials,PubMed,ISI Web of Science,Embase,Scopus,and Google scholar were searched up to December 2018,for relevant clinical trials.Mean changes in fasting blood sugar(FBS),serum insulin,and homeostasis model assessment of insulin resistance(HOMA-IR)were extracted.Results:The pooled analysis of nine studies showed that there was no significant difference between AA/AT and TT genotypes in FBS(weighted mean difference[WMD]=0.01,95%confidence interval[CI]:-1.08,1.10,P=0.984)and serum insulin(WMD=0.20,95%CI:-0.85,1.26;P=0.707)after intervention hypocaloric diets.The overweight/obese participants in AA/AT group showed the greatest reduction in HOMA-IR compared with TT genotype following intervention,and this difference was not statistically significant(WMD=-0.38,95%CI:-0.94,0.16,P=0.167).Conclusion:This meta-analysis suggests that there was no significant difference between AA/AT and TT genotypes of FTO-rs9939609 on FBS,serum insulin level,and insulin resistance in response to hypocaloric diets.
基金supported by the National Natural Science Foundation Project of China(No.82070951,82271078 and 81873678)the Innovative Research Group Project of Chongqing Education Commission(China)(No.CXQT19015)+5 种基金the Natural Science Foundation Project of Chongqing,China(No.cstc2019jcyjmsxmx0120)the Innovation Supporting Plan of Overseas Study of Chongqing,China(No.cx2018010)the Chongqing Education Commission(China)(No.KJQN202000406)the National Key Clinical Specialties Construction Program of China,Chongqing Branch of National Clinical Research Center for Ocular Diseasesthe Chongqing Key Laboratory of Ophthalmology(China)(CSTC,No.2008CA5003)Natural Science Foundation Project of Chongqing Medical University(China)(No.W0047).
文摘Uveitis,a vision-threatening inflammatory disease worldwide,is closely related to resident microglia.Retinal microglia are the main immune effector cells with strong plasticity,but their role in uveitis remains unclear.N6-methyladenosine(m^(6)A)modification has been proven to be involved in the immune response.Therefore,we in this work aimed to identify the potentially crucial m^(6)A regulators of microglia in uveitis.Through the single-cell sequencing(scRNA-seq)analysis and experimental verification,we found a significant decrease in the expression of fat mass and obesity-associated protein(FTO)in retinal microglia of uveitis mice and human microglia clone 3(HMC3)cells with inflammation.Additionally,FTO knockdown was found to aggravate the secretion of inflammatory factors and the mobility/chemotaxis of microglia.Mechanistically,the RNA-seq data and rescue experiments showed that glypican 4(GPC4)was the target of FTO,which regulated microglial inflammation mediated by the TLR4/NF-κB pathway.Moreover,RNA stability assays indicated that GPC4 upregulation was mainly regulated by the downregulation of the m^(6)A“reader”YTH domain family protein 3(YTHDF3).Finally,the FTO inhibitor FB23-2 further exacerbated experimental autoimmune uveitis(EAU)inflammation by promoting the GPC4/TLR4/NF-κB signaling axis,and this could be attenuated by the TLR4 inhibitor TAK-242.Collectively,a decreased FTO could facilitate microglial inflammation in EAU,suggesting that the restoration or activation of FTO function may be a potential therapeutic strategy for uveitis.
基金supported by the National Natural Science Foundation of China(31371760)the Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD)
文摘This study explored how bitter melon powder （BMP） alters the colonic microenvironment during the development of obesity-associated fatty liver in rats. We observed that BMP effectively inhibited the body weight gain and lipid accumulation in the liver, ameliorated glucose intolerance, and increased the colon weight after an 8-week treatment compared to that in the high-fat diet （HFD） group. BMP significantly decreased fecal water toxicity towards HT-29 cells, as revealed by the cell counting kit （CCK）-8 assay results, and the mRNA expression of Toll-like receptor 4 （TLR4） in colon mucosa. Additionally, gut permeability in the BMP group was restored to normal levels. Finally, BMP alleviated the inflammatory state of the rat colon mucosa and liver tissues as well as the systemic inflammation.
基金This study was supported by the Natural Science Foundation of Guangdong Provincial(2019A1515011911)the Research Program of Shenzhen Innovation Council(JCYJ20200109140208058)+1 种基金the Sanming Project of Medicine in Shenzhen(SZSM202111012)the Oral and Maxillofacial Surgery Team,Professor Yu Guangyan,Stomatological Hospital Peking University,Guangdong Provincial High-Level Clinical Key Specialty(Shenzhen Matching Construction Fund)(Grant No.SZGSP008).
文摘N6-methyladenosine(m6A)modification is the most widespread and conserved internal mRNA modification in mammalian cells.It greatly affects genetic regulation by enhancing the involvement of diverse cellular enzymes and thus,plays a significant role in basic life processes.Numerous studies on m6A modification identified FTO as a crucial demethylase that participates in various biological processes.Not only does FTO play a pivotal role in obesity-related conditions,but it also influences the occurrence,development,and prognosis of several cancers,such as acute myeloid leukemia,breast cancer,liver cancer,and lung cancer.Moreover,FTO also shows a close association with immunity and viral infections.This article summarized the molecular mechanism of FTO in tumorigenesis and tumor progression.
文摘Background:N6-methyladenosine(m6A)RNA modification has been demonstrated to be a significant regulatory process in the progression of various tumors,including breast cancer.Fat mass and obesity-associated(FTO)enzyme,initially known as the obesity-related protein,is the first identified m6A demethylase.However,the relationship between FTO and breast cancer remains controversial.In this study,we aimed to elucidate the role and clinical significance of FTO in breast cancer and to explore the underlying mechanism.Methods:We first investigated the expression of FTO in breast cancer cell lines and tissues by quantitative reverse transcription-PCR(qRT-PCR),Western blotting,and immunohistochemistry.Wound healing assay and Transwell assay were performed to determine the migration and invasion abilities of SKBR3 and MDAMB453 cells with either knockdown or overexpression of FTO.RNA sequencing(RNA-seq)was conducted to decipher the downstream targets of FTO.qRT-PCR,luciferase reporter assay,and Western blotting were employed to confirm the existence of the FTO/miR-181b-3p/ARL5B axis.The biological function of ADP ribosylation factor like GTPase 5B(ARL5B)in breast cancer cells was evaluated by wound healing assay and Transwell invasion assay.Results:High FTO expression was observed in human epidermal growth factor receptor 2(HER2)-positive breast cancer,predicting advanced progression(tumor size[P<0.001],nuclear grade[P=0.001],peritumoral lymphovascular invasion[P<0.001),lymph node metastasis[P=0.002],and TNM stage[P=0.001])and poor prognosis.Moreover,FTO promoted cell invasion and migration in vitro.Mechanistically,RNA-seq and further confirmation studies suggested that FTO up-regulated ARL5B by inhibiting miR-181b-3p.We further verified that ARL5B also displayed carcinogenic activity in breast cancer cells.Conclusion:Our work demonstrated the carcinogenic activity of FTO in promoting the invasion and migration of breast cancer cells via the FTO/miR-181b-3p/ARL5B signaling pathway.
文摘肥胖相关蛋白(fat mass and obesity-associated protein,FTO)是一种位于染色体16q12.2上的N6-甲基腺苷(m^6A)去甲基酶,以往的研究证实FTO可通过3’非翻译区域调节下游的m^6A水平来影响肥胖。随着研究的不断深入,研究者们发现,m^6A甲基化这一表观遗传修饰能通过调控肿瘤基因、抑肿瘤基因的mRNA分子的表达水平调控肿瘤的发生发展。FTO作为m^6A修饰的重要组成部分,参与调控多种肿瘤的发生、发展及其预后。目前研究表明,FTO能够通过不同方式(影响肿瘤细胞生长和增殖、抑制细胞分化、干预肿瘤干细胞自我更新、影响肿瘤转移和放化疗敏感性等)参与调控多种肿瘤发生发展。因此,FTO有望在不久的将来成为诊断和治疗肿瘤的新靶点,特别是针对某些特定类型的肿瘤,如急性髓系白血病、胶质母细胞癌和乳腺癌等,这对于肿瘤的诊疗具有重要的理论意义和应用价值。本文拟通过对目前有关FTO的研究进行整理和分析,对FTO在肿瘤中的作用及其研究进展进行了综述。
文摘目的评价脂肪量与肥胖相关基因(fat mass and obesity-associated gene,FTO)的多个单核苷酸多态性位点(single nucleotide polymorphisms,SNP)与乳腺癌发病的相关性。方法全面检索Pubmed、Embase、Web of science、中国知网(CNKI)、万方数据库及中国生物医学文献数据库(CBM),获取11个FTO基因多态性与乳腺癌易感性的病例-对照研究,对不同SNP位点采用等位基因位点、共显性遗传模型、显性遗传模型、隐性遗传模型分别评价乳腺癌发病的相对危险度,并对异质性较大的遗传模型,进行不同人种的亚组分析。运用Meta分析方法综合评价FTO的SNP位点(rs9939609、rs1477196、rs1121980)与乳腺癌的相关性。结果共有6篇病例-对照研究文献被纳入,包括2994例乳腺癌患者和3699名健康对照,Meta分析结果显示:rs1477196基因多态性在显性遗传模型中与乳腺癌具有相关性(OR=1.241,95%CI为1.035~1.488,P=0.019);rs9939609和rs1121980基因多态性与乳腺癌均无明显相关性(OR=1.062,95%CI为0.934~1.208,P=0.36)。人种亚组分析则显示rs1477196的G等位基因在亚洲人中与乳腺癌显著相关(OR=1.305,95%CI为1.085~1.569,P=0.005),但与高加索人(OR=1.136,95%CI为0.641~2.014,P=0.662)和混合人种(OR=1.131,95%CI为0.809~1.583,P=0.472)均无相关性。结论 FTO多态性与乳腺癌的易感性在不同遗传模型及人种中有差异。亚洲人中rs1477196的G等位基因与乳腺癌发病呈正相关。
