目的探讨17 p 13.3微缺失综合征的临床表型、拷贝数变异、治疗及预后。方法回顾性分析5例17p13.3微缺失综合征患儿临床资料、全外显子组测序结果以及治疗效果。结果5例患儿均表现为身材矮小,例3~5合并有心血管异常。全外显子组测序提示...目的探讨17 p 13.3微缺失综合征的临床表型、拷贝数变异、治疗及预后。方法回顾性分析5例17p13.3微缺失综合征患儿临床资料、全外显子组测序结果以及治疗效果。结果5例患儿均表现为身材矮小,例3~5合并有心血管异常。全外显子组测序提示所有的患儿均存在17p13.3染色体片段缺失,缺失大小为433~1536 kb,主要包括YWHAE、CRK基因,但不包括PAFAH1B1基因。在排除了生长激素禁忌证后,4例接受了重组人生长激素治疗。矮小症患儿的身高在应用重组人生长激素治疗后初期得到改善,但后期治疗效果欠佳。2例满足手术指征而接受外科手术以纠正先天性心脏畸形。结论17p13.3染色体片段缺失可导致17p13.3微缺失综合征,通过全外显子组测序,可以提高对于存在先天性心脏畸形和/或矮小症的儿童的诊断率,及时采取心血管及身高方面的治疗有助于改善患儿预后。展开更多
Objective: Genome-wide association studies(GWAS) have identified over 150 risk loci linked to colorectal cancer(CRC), including the 17p13.3 locus with the tag single nucleotide polymorphism(SNP) rs12603526 in the Asia...Objective: Genome-wide association studies(GWAS) have identified over 150 risk loci linked to colorectal cancer(CRC), including the 17p13.3 locus with the tag single nucleotide polymorphism(SNP) rs12603526 in the Asian population. However, the specific causal gene and the functional regulatory mechanisms in this region remain unresolved, necessitating further investigation to elucidate the underlying mechanisms of CRC.Methods: We employed an RNA interference-based functional approach to identify genes critical for CRC cell proliferation at the GWAS locus 17p13.3. Bioinformatic fine-mapping analysis was conducted to prioritize causal variants. A large-scale study involving 7,013 cases and 7,329 controls from a Chinese population, along with another cohort of 5,158 cases and 20,632 controls from the UK Biobank, was performed to validate the association between the candidate variant and the gene. A series of biological experiments was conducted to explore the function of the candidate gene and its regulatory mechanisms.Results: We identified FAM57A as a key oncogene that promotes CRC cell proliferation, and confirmed its carcinogenic role through in vitro proliferation assays. The variant rs526835 was prioritized as a causal candidate for CRC risk, located in a functional region with enhancer properties, and showed a significant quantitative association with FAM57A expression. The rs526835 [T] variant was associated with a 1.17-fold increase in CRC risk [95%confidence interval(95% CI): 1.11-1.23, P=1.23×10^(−9)] in the large-scale Chinese cohort, which was further corroborated in the UK Biobank cohort. Mechanistically, we demonstrated that rs526835 enhances a promoterenhancer interaction mediated by the transcription factor JUN, leading to increased expression of FAM57A.Conclusions: We reveal the underlying mechanisms of CRC predisposition at the GWAS locus 17p13.3.Additionally, our findings highlight the critical role of FAM57A in CRC pathogenesis and introduce a novel enhancer-promoter interaction between FAM57A and rs526835, which could inform future precision prevention and personalized cancer therapies.展开更多
The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)inductio...The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)induction causing NSCLC cell metastasis,the underlying mechanism remains unclear.In the study,we found that IL-17 receptor A(IL-17RA),p300,p-STAT3,Ack-STAT3,and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17.p300,STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3,Ack-STAT3 and MMP19 level as well as the cell migration and invasion.Mechanism investigation revealed that STAT3 and p300 bound to the same region(−544 to−389 nt)of MMP19 promoter,and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity,p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17.Meanwhile,p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact,synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion.Besides,the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300,STAT3 or MMP19 gene plus IL-17 treatment,the nodule number,and MMP19,Ack-STAT3,or p-STAT3 production in the lung metastatic nodules were all alleviated.Collectively,these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation,which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.展开更多
目的探讨EBV mi R-BART17-3p影响原发免疫性血小板减少症(ITP)患儿Treg/Th17平衡的机制。方法收集ITP患儿(ITP组,20例)和健康儿童(对照组,20例)外周血并分离CD_(4)^(+)T细胞。采用实时荧光定量聚合酶链式反应法、Western blot法、酶联...目的探讨EBV mi R-BART17-3p影响原发免疫性血小板减少症(ITP)患儿Treg/Th17平衡的机制。方法收集ITP患儿(ITP组,20例)和健康儿童(对照组,20例)外周血并分离CD_(4)^(+)T细胞。采用实时荧光定量聚合酶链式反应法、Western blot法、酶联免疫吸附法检测EBV mi R-BART17-3p、T细胞免疫球蛋白黏蛋白3(Tim-3)、叉头框蛋白P3(Fox P3)、白细胞介素17A(IL-17A)和转化生长因子-β(TGF-β)的m RNA、蛋白表达水平及含量。采用双荧光素酶报告基因实验考察EBV mi R-BART17-3p对Tim-3表达水平的影响。将15只BALB/C小鼠随机分为空白对照组、模型组、观察组,各5只。腹腔注射抗血小板抗体MWReg30以复制ITP小鼠模型,建模4 d后观察组小鼠予尾静脉注射携带EBV mi R-BART17-3p inhibitor的腺病毒载体。细胞染色并观察形态,检测外周血中TGF-β、IL-17A含量及血小板计数,采用流式细胞仪分别检测CD_(4)^(+)T细胞中Th17和Treg水平,并计算二者百分比。结果与对照组比较,ITP组患儿外周血EBV mi R-BART17-3p表达水平显著升高,Tim-3和TGF-βm RNA表达水平显著降低(P<0.05);Tim-3 m RNA表达水平与EBV mi R-BART17-3p表达水平呈显著负相关(r=-0.732,P<0.001)。Tim-3慢病毒载体p LKO.1-sh-Tim-3(sh-Tim-3)可显著降低Tim-3、Fox P3、TGF-β水平(P<0.05)。mi R-BART17-3p mimic显著升高了CD_(4)^(+)T细胞中mi R-BART17-3p的表达水平,并显著降低了Tim-3、Fox P3、TGF-βm RNA和蛋白表达水平(P<0.05);mi R-BART17-3p mimic可显著降低TGF-β含量,Tim-3+mi R-BART17-3p过表达逆转了mi R-BART17-3p mimic对TGF-β的抑制作用。动物实验结果显示,沉默EBV mi R-BART17-3p可促进Treg分化,减少脾脏和骨髓组织中的巨核细胞计数,并显著增加外周血中血小板计数。结论EBV mi R-BART17-3p可通过Fox P3/Tim-3途径调节ITP患儿Treg/Th17的免疫失衡。展开更多
文摘目的探讨17 p 13.3微缺失综合征的临床表型、拷贝数变异、治疗及预后。方法回顾性分析5例17p13.3微缺失综合征患儿临床资料、全外显子组测序结果以及治疗效果。结果5例患儿均表现为身材矮小,例3~5合并有心血管异常。全外显子组测序提示所有的患儿均存在17p13.3染色体片段缺失,缺失大小为433~1536 kb,主要包括YWHAE、CRK基因,但不包括PAFAH1B1基因。在排除了生长激素禁忌证后,4例接受了重组人生长激素治疗。矮小症患儿的身高在应用重组人生长激素治疗后初期得到改善,但后期治疗效果欠佳。2例满足手术指征而接受外科手术以纠正先天性心脏畸形。结论17p13.3染色体片段缺失可导致17p13.3微缺失综合征,通过全外显子组测序,可以提高对于存在先天性心脏畸形和/或矮小症的儿童的诊断率,及时采取心血管及身高方面的治疗有助于改善患儿预后。
基金supported by the Program of National Science Fund for Distinguished Young Scholars of China(No.81925032)Key Program of National Natural Science Foundation of China(No.82130098)National Natural Science Foundation of China(No.82304232)。
文摘Objective: Genome-wide association studies(GWAS) have identified over 150 risk loci linked to colorectal cancer(CRC), including the 17p13.3 locus with the tag single nucleotide polymorphism(SNP) rs12603526 in the Asian population. However, the specific causal gene and the functional regulatory mechanisms in this region remain unresolved, necessitating further investigation to elucidate the underlying mechanisms of CRC.Methods: We employed an RNA interference-based functional approach to identify genes critical for CRC cell proliferation at the GWAS locus 17p13.3. Bioinformatic fine-mapping analysis was conducted to prioritize causal variants. A large-scale study involving 7,013 cases and 7,329 controls from a Chinese population, along with another cohort of 5,158 cases and 20,632 controls from the UK Biobank, was performed to validate the association between the candidate variant and the gene. A series of biological experiments was conducted to explore the function of the candidate gene and its regulatory mechanisms.Results: We identified FAM57A as a key oncogene that promotes CRC cell proliferation, and confirmed its carcinogenic role through in vitro proliferation assays. The variant rs526835 was prioritized as a causal candidate for CRC risk, located in a functional region with enhancer properties, and showed a significant quantitative association with FAM57A expression. The rs526835 [T] variant was associated with a 1.17-fold increase in CRC risk [95%confidence interval(95% CI): 1.11-1.23, P=1.23×10^(−9)] in the large-scale Chinese cohort, which was further corroborated in the UK Biobank cohort. Mechanistically, we demonstrated that rs526835 enhances a promoterenhancer interaction mediated by the transcription factor JUN, leading to increased expression of FAM57A.Conclusions: We reveal the underlying mechanisms of CRC predisposition at the GWAS locus 17p13.3.Additionally, our findings highlight the critical role of FAM57A in CRC pathogenesis and introduce a novel enhancer-promoter interaction between FAM57A and rs526835, which could inform future precision prevention and personalized cancer therapies.
基金National Natural Science Foundation of China(Grants Numbers 81902878 and 81971468).
文摘The cancer cell metastasis is a major death reason for patients with non-small cell lung cancer(NSCLC).Although researchers have disclosed that interleukin 17(IL-17)can increase matrix metalloproteinases(MMPs)induction causing NSCLC cell metastasis,the underlying mechanism remains unclear.In the study,we found that IL-17 receptor A(IL-17RA),p300,p-STAT3,Ack-STAT3,and MMP19 were up-regulated both in NSCLC tissues and NSCLC cells stimulated with IL-17.p300,STAT3 and MMP19 overexpression or knockdown could raise or reduce IL-17-induced p-STAT3,Ack-STAT3 and MMP19 level as well as the cell migration and invasion.Mechanism investigation revealed that STAT3 and p300 bound to the same region(−544 to−389 nt)of MMP19 promoter,and p300 could acetylate STAT3-K631 elevating STAT3 transcriptional activity,p-STAT3 or MMP19 expression and the cell mobility exposed to IL-17.Meanwhile,p300-mediated STAT3-K631 acetylation and its Y705-phosphorylation could interact,synergistically facilitating MMP19 gene transcription and enhancing cell migration and invasion.Besides,the animal experiments exhibited that the nude mice inoculated with NSCLC cells by silencing p300,STAT3 or MMP19 gene plus IL-17 treatment,the nodule number,and MMP19,Ack-STAT3,or p-STAT3 production in the lung metastatic nodules were all alleviated.Collectively,these outcomes uncover that IL-17-triggered NSCLC metastasis involves up-regulating MMP19 expression via the interaction of STAT3-K631 acetylation by p300 and its Y705-phosphorylation,which provides a new mechanistic insight and potential strategy for NSCLC metastasis and therapy.
文摘目的探讨EBV mi R-BART17-3p影响原发免疫性血小板减少症(ITP)患儿Treg/Th17平衡的机制。方法收集ITP患儿(ITP组,20例)和健康儿童(对照组,20例)外周血并分离CD_(4)^(+)T细胞。采用实时荧光定量聚合酶链式反应法、Western blot法、酶联免疫吸附法检测EBV mi R-BART17-3p、T细胞免疫球蛋白黏蛋白3(Tim-3)、叉头框蛋白P3(Fox P3)、白细胞介素17A(IL-17A)和转化生长因子-β(TGF-β)的m RNA、蛋白表达水平及含量。采用双荧光素酶报告基因实验考察EBV mi R-BART17-3p对Tim-3表达水平的影响。将15只BALB/C小鼠随机分为空白对照组、模型组、观察组,各5只。腹腔注射抗血小板抗体MWReg30以复制ITP小鼠模型,建模4 d后观察组小鼠予尾静脉注射携带EBV mi R-BART17-3p inhibitor的腺病毒载体。细胞染色并观察形态,检测外周血中TGF-β、IL-17A含量及血小板计数,采用流式细胞仪分别检测CD_(4)^(+)T细胞中Th17和Treg水平,并计算二者百分比。结果与对照组比较,ITP组患儿外周血EBV mi R-BART17-3p表达水平显著升高,Tim-3和TGF-βm RNA表达水平显著降低(P<0.05);Tim-3 m RNA表达水平与EBV mi R-BART17-3p表达水平呈显著负相关(r=-0.732,P<0.001)。Tim-3慢病毒载体p LKO.1-sh-Tim-3(sh-Tim-3)可显著降低Tim-3、Fox P3、TGF-β水平(P<0.05)。mi R-BART17-3p mimic显著升高了CD_(4)^(+)T细胞中mi R-BART17-3p的表达水平,并显著降低了Tim-3、Fox P3、TGF-βm RNA和蛋白表达水平(P<0.05);mi R-BART17-3p mimic可显著降低TGF-β含量,Tim-3+mi R-BART17-3p过表达逆转了mi R-BART17-3p mimic对TGF-β的抑制作用。动物实验结果显示,沉默EBV mi R-BART17-3p可促进Treg分化,减少脾脏和骨髓组织中的巨核细胞计数,并显著增加外周血中血小板计数。结论EBV mi R-BART17-3p可通过Fox P3/Tim-3途径调节ITP患儿Treg/Th17的免疫失衡。
