The SMAD2/miR-4256/HDAC5/p16^(INK4a) signaling axis contributes to gastric cancer progression  

作　　者：MIN WANG HAILIANG ZHAO WEIWEI CHEN CAIQUN BIE JINYING YANG WENRUI CAI CHUTIAN WU YANFANG CHEN SHUFEN FENG YING SHI YUTING LI HUIJUN TANG LIXIAN ZHONG LILIANGZI GUO SISI CHEN LINJING LONG SHAOHUI TANG 

机构地区：[1]Department of Gastroenterology,The First Affiliated Hospital,Jinan University,Guangzhou,510632,China [2]Department of Gastroenterology,Affiliated Hospital of Youjiang Medical University for Nationalities,Baise,533000,China [3]Department of Gastroenterology,The First People’s Hospital of Zunyi,The Third Affiliated Hospital of Zunyi Medical University,Zunyi,563099,China [4]Department of Gastroenterology,Shenzhen Hospital of Integrated Traditional Chinese and Western Medicine,Shenzhen,518104,China [5]Department of Gastroenterology,The Fifth Affiliated Hospital of Guangzhou Medical University,Guangzhou,510799,China

出　　处：《Oncology Research》2023年第4期515-541,共27页肿瘤学研究（英文）

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;Animalinvolved experimental protocols were compliance with guidelines and licenses;approved by the Laboratory Animal Center of Jinan University(20220225-65).

摘　　要：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.

关 键 词：Gastric cancer miR-4256 SMAD2 HDAC5 p16^(INK4a) 

分 类 号：R73[医药卫生—肿瘤]