The dysregulation of exosomal microRNAs(miRNAs)plays a crucial role in the development and progression of cancer.This study investigated the role of a newly identified serum exosomal miRNA miR-4256 in gastric cancer(G...The dysregulation of exosomal microRNAs(miRNAs)plays a crucial role in the development and progression of cancer.This study investigated the role of a newly identified serum exosomal miRNA miR-4256 in gastric cancer(GC)and the underlying mechanisms.The differentially expressed miRNAs were firstly identified in serum exosomes of GC patients and healthy individuals using next-generation sequencing and bioinformatics.Next,the expression of serum exosomal miR-4256 was analyzed in GC cells and GC tissues,and the role of miR-4256 in GC was investigated by in vitro and in vivo experiments.Then,the effect of miR-4256 on its downstream target genes HDAC5/p16^(INK4a) was studied in GC cells,and the underlying mechanisms were evaluated using dual luciferase reporter assay and Chromatin Immunoprecipitation(ChIP).Additionally,the role of the miR-4256/HDAC5/p16^(INK4a) axis in GC was studied using in vitro and in vivo experiments.Finally,the upstream regulators SMAD2/p300 that regulate miR-4256 expression and their role in GC were explored using in vitro experiments.miR-4256 was the most significantly upregulated miRNA and was overexpressed in GC cell lines and GC tissues;in vitro and in vivo results showed that miR-4256 promoted GC growth and progression.Mechanistically,miR-4256 enhanced HDAC5 expression by targeting the promoter of the HDAC5 gene in GC cells,and then restrained the expression of p16^(INK4a) through the epigenetic modulation of HDAC5 at the p16INK4a promoter.Furthermore,miR-4256 overexpression was positively regulated by the SMAD2/p300 complex in GC cells.Our data indicate that miR-4256 functions as an oncogene in GC via the SMAD2/miR-4256/HDAC5/p16^(INK4a) axis,which participates in GC progression and provides novel therapeutic and prognostic biomarkers for GC.展开更多
背景与目的:高危型人乳头状瘤病毒(high-risk human papillomavirus,HR-HPV)是宫颈癌最主要的致病因素,目前研究发现,在宫颈上皮癌变过程中,P16INK4A的异常表达和HR-HPV感染密切相关;同时,另一抑癌基因PTEN也参与了宫颈上皮肿瘤的形成...背景与目的:高危型人乳头状瘤病毒(high-risk human papillomavirus,HR-HPV)是宫颈癌最主要的致病因素,目前研究发现,在宫颈上皮癌变过程中,P16INK4A的异常表达和HR-HPV感染密切相关;同时,另一抑癌基因PTEN也参与了宫颈上皮肿瘤的形成。本研究旨在探讨宫颈上皮癌变过程中P16INK4A、PTEN表达与HR-HPV感染的关系及其意义。方法:应用免疫组织化学方法检测P16INK4A蛋白和PTEN蛋白在30例正常宫颈组织、11例原位癌、24例宫颈浸润癌组织中的表达。用第二代杂交捕获法(HC-2)检测每一病例的13种HR-HPV DNA。结果:HR-HPV和P16INK4A阳性率浸润癌组(91.7%、87.5%)和原位癌组(90.9%、81.8%)都明显高于正常宫颈组(30.0%、6.7%),差异有统计学意义(P<0.001)。P16INK4A过表达(中、强阳性)和HR-HPV阳性同时出现有30例,其中原位癌组9例,浸润癌组21例;两者同时阴性有23例,其中正常宫颈组20例,原位癌组1例,浸润癌组2例。相关性分析结果显示,HR-HPV感染与P16INK4A表达呈正相关(rs=0.690,P<0.001)。26例PTEN中、强阳性表达均在正常宫颈组,其阳性率在浸润癌组(37.5%)和原位癌组(36.4%)明显低于正常宫颈组(83.3%),差异有统计学意义(P<0.01)。相关性分析证实,HR-HPV感染与PTEN表达的相关性无统计学意义(rs=-0.174,P=0.167)。结论:在HR-HPV感染的宫颈癌中,P16INK4A出现过表达,其蛋白的肿瘤抑制功能不明显;PTEN独立于HR-HPV途径,以其功能下调促进宫颈癌的发生、发展。展开更多
基金The studies involving human participants were approved by The First Affiliated Hospital of Jinan University Ethics Committee(KY-2021-095)The participants provided their written informed consent to participate in this study+1 种基金Animalinvolved experimental protocols were compliance with guidelines and licensesapproved by the Laboratory Animal Center of Jinan University(20220225-65).
文摘The dysregulation of exosomal microRNAs(miRNAs)plays a crucial role in the development and progression of cancer.This study investigated the role of a newly identified serum exosomal miRNA miR-4256 in gastric cancer(GC)and the underlying mechanisms.The differentially expressed miRNAs were firstly identified in serum exosomes of GC patients and healthy individuals using next-generation sequencing and bioinformatics.Next,the expression of serum exosomal miR-4256 was analyzed in GC cells and GC tissues,and the role of miR-4256 in GC was investigated by in vitro and in vivo experiments.Then,the effect of miR-4256 on its downstream target genes HDAC5/p16^(INK4a) was studied in GC cells,and the underlying mechanisms were evaluated using dual luciferase reporter assay and Chromatin Immunoprecipitation(ChIP).Additionally,the role of the miR-4256/HDAC5/p16^(INK4a) axis in GC was studied using in vitro and in vivo experiments.Finally,the upstream regulators SMAD2/p300 that regulate miR-4256 expression and their role in GC were explored using in vitro experiments.miR-4256 was the most significantly upregulated miRNA and was overexpressed in GC cell lines and GC tissues;in vitro and in vivo results showed that miR-4256 promoted GC growth and progression.Mechanistically,miR-4256 enhanced HDAC5 expression by targeting the promoter of the HDAC5 gene in GC cells,and then restrained the expression of p16^(INK4a) through the epigenetic modulation of HDAC5 at the p16INK4a promoter.Furthermore,miR-4256 overexpression was positively regulated by the SMAD2/p300 complex in GC cells.Our data indicate that miR-4256 functions as an oncogene in GC via the SMAD2/miR-4256/HDAC5/p16^(INK4a) axis,which participates in GC progression and provides novel therapeutic and prognostic biomarkers for GC.
文摘背景与目的:高危型人乳头状瘤病毒(high-risk human papillomavirus,HR-HPV)是宫颈癌最主要的致病因素,目前研究发现,在宫颈上皮癌变过程中,P16INK4A的异常表达和HR-HPV感染密切相关;同时,另一抑癌基因PTEN也参与了宫颈上皮肿瘤的形成。本研究旨在探讨宫颈上皮癌变过程中P16INK4A、PTEN表达与HR-HPV感染的关系及其意义。方法:应用免疫组织化学方法检测P16INK4A蛋白和PTEN蛋白在30例正常宫颈组织、11例原位癌、24例宫颈浸润癌组织中的表达。用第二代杂交捕获法(HC-2)检测每一病例的13种HR-HPV DNA。结果:HR-HPV和P16INK4A阳性率浸润癌组(91.7%、87.5%)和原位癌组(90.9%、81.8%)都明显高于正常宫颈组(30.0%、6.7%),差异有统计学意义(P<0.001)。P16INK4A过表达(中、强阳性)和HR-HPV阳性同时出现有30例,其中原位癌组9例,浸润癌组21例;两者同时阴性有23例,其中正常宫颈组20例,原位癌组1例,浸润癌组2例。相关性分析结果显示,HR-HPV感染与P16INK4A表达呈正相关(rs=0.690,P<0.001)。26例PTEN中、强阳性表达均在正常宫颈组,其阳性率在浸润癌组(37.5%)和原位癌组(36.4%)明显低于正常宫颈组(83.3%),差异有统计学意义(P<0.01)。相关性分析证实,HR-HPV感染与PTEN表达的相关性无统计学意义(rs=-0.174,P=0.167)。结论:在HR-HPV感染的宫颈癌中,P16INK4A出现过表达,其蛋白的肿瘤抑制功能不明显;PTEN独立于HR-HPV途径,以其功能下调促进宫颈癌的发生、发展。
