Exosomal miR-17-5p derived from epithelial cells is involved in aberrant epithelium-fibroblast crosstalk and induces the development of oral submucosal fibrosis  

作　　者：Changqing Xie Liang Zhong Hui Feng Rifu Wang Yuxin Shi Yonglin Lv Yanjia Hu Jing Li Desheng Xiao Shuang Liu Qianming Chen Yongguang Tao 

机构地区：[1]NHC Key Laboratory of Carcinogenesis,Cancer Research Institute,School of Basic Medicine Sciences,Central South University,Changsha,China [2]Hospital of Stomatology and Key Laboratory of Oral Biomedical Research of Zhejiang Province,School of Stomatology,Zhejiang University School of Medicine,Hangzhou,China [3]Hunan Key Laboratory of Oral Health Research&Hunan 3D Printing Engineering Research Center of Oral Care&Hunan Clinical Research Center of Oral Major Diseases and Oral Health&Xiangya Stomatological Hospital&Xiangya School of Stomatology,Central South University,Changsha,China [4]State Key Laboratory of Oral Diseases&National Center for Stomatology&National Clinical Research Center for Oral Diseases&Chinese Academy of Medical Sciences Research Unit of Oral Carcinogenesis and Management,West China Hospital of Stomatology,Sichuan University,Chengdu,China [5]Department of Oncology,Institute of Medical Sciences,National Clinical Research Center for Geriatric Disorders,Xiangya Hospital,Central South University,Changsha,China

出　　处：《International Journal of Oral Science》2024年第4期671-684,共14页国际口腔科学杂志(英文版)

基　　金：supported by grants from the National Natural Science Foundation of China(82201079);the Natural Science Foundation of Hunan Province,China(2023JJ40881);the Major Project of Natural Science Foundation of Hunan Province(Open Competition,2021JC0002);the Fundamental Research Funds for the Central Universities of Central South University(2023ZZTS0582)。

摘　　要：Oral submucous fibrosis(OSF)is a chronic and inflammatory mucosal disease caused by betel quid chewing,which belongs to oral potentially malignant disorders.Abnormal fibroblast differentiation leading to disordered collagen metabolism is the core process underlying OSF development.The epithelium,which is the first line of defense against the external environment,can convert external signals into pathological signals and participate in the remodeling of the fibrotic microenvironment.However,the specific mechanisms by which the epithelium drives fibroblast differentiation remain unclear.In this study,we found that Arecolineexposed epithelium communicated with the fibrotic microenvironment by secreting exosomes.MiR-17-5p was encapsulated in epithelial cell-derived exosomes and absorbed by fibroblasts,where it promoted cell secretion,contraction,migration and fibrogenic marker(α-SMA and collagen type I)expression.The underlying molecular mechanism involved miR-17-5p targeting Smad7 and suppressing the degradation of TGF-βreceptor 1(TGFBR1)through the E3 ubiquitination ligase WWP1,thus facilitating downstream TGF-βpathway signaling.Treatment of fibroblasts with an inhibitor of miR-17-5p reversed the contraction and migration phenotypes induced by epithelial-derived exosomes.Exosomal miR-17-5p was confirmed to function as a key regulator of the phenotypic transformation of fibroblasts.In conclusion,we demonstrated that Arecoline triggers aberrant epitheliumfibroblast crosstalk and identified that epithelial cell-derived miR-17-5p mediates fibroblast differentiation through the classical TGF-βfibrotic pathway,which provided a new perspective and strategy for the diagnosis and treatment of OSF.

关 键 词：EPITHELIUM metabolism diagnosis 

分 类 号：R781.5[医药卫生—口腔医学]