Runx2 activates hepatic stellate cells to promote liver fibrosis via transcriptionally regulating <i>Itgav</i> expression

作者全名："Zhong, Li; Zhao, Jinqiu; Huang, Lu; Liu, Yi; Pang, Xiaoxiao; Zhan, Ke; Li, Shan; Xue, Qian; Pan, Xiaoli; Deng, Liang"

作者地址："[Zhong, Li; Zhan, Ke; Li, Shan; Xue, Qian; Deng, Liang] Chongqing Med Univ, Affiliated Hosp 1, Dept Gastroenterol, Chongqing, Peoples R China; [Zhong, Li; Liu, Yi] Chongqing Med Univ, Affiliated Hosp 2, Dept Gastroenterol & Hepatol, Chongqing, Peoples R China; [Zhao, Jinqiu] Chongqing Med Univ, Affiliated Hosp 1, Dept Infect Dis, Chongqing, Peoples R China; [Huang, Lu] Chongqing Key Lab Child Infect & Immun, Chongqing, Peoples R China; [Huang, Lu] Dept Pediat Res Inst, Chongqing, Peoples R China; [Huang, Lu] Chongqing Med Univ, Childrens Hosp, Key Lab Child Dev & Disorders, Minist Educ, Chongqing, Peoples R China; [Pang, Xiaoxiao] Chongqing Key Lab Oral Dis & Biomed Sci, Chongqing, Peoples R China; [Pang, Xiaoxiao] Chongqing Med Univ, Stomatol Hosp, Chongqing Municipal Key Lab Oral Biomed Engn Highe, Chongqing, Peoples R China; [Pan, Xiaoli] Huazhong Univ Sci & Technol, Union Hosp, Tongji Med Coll, Dept Gastroenterol, Wuhan, Peoples R China"

通信作者："Deng, L (通讯作者)，Chongqing Med Univ, Affiliated Hosp 1, Dept Gastroenterol, Chongqing, Peoples R China."

来源：CLINICAL AND TRANSLATIONAL MEDICINE

ESI学科分类：CLINICAL MEDICINE

WOS号：WOS:001024948300001

JCR分区：Q1

影响因子：7.9

年份：2023

卷号：13

期号：7

开始页：　

结束页：　

文献类型：Article

关键词：TGF-beta 1; Runx2; PKA; Itgav; HSC activation

摘要："Backgrounds and aims: As a central event during liver fibrosis, hepatic stellate cells (HSC) have been thought to be a potential therapeutic target for liver fibrosis. Previous studies have shown that runt-related transcription factor 2 (Runx2) is associated with the development of non-alcoholic fatty liver disease, while its specific role in HSC activation and hepatic fibrosis remains elusive. Approach and results: In this study, we found that Runx2 expression was significantly upregulated in human liver fibrosis with different aetiologies. Runx2 expression was also gradually elevated in mouse liver during fibrosis, and Runx2 was mainly expressed in the activated HSC. Knockdown of Runx2 in HSC markedly alleviated CCl4-induced, 3,5-diethoxycarbonyl-1,4-dihydrocollidine-induced or methionine-choline deficient (MCD)-induced liver fibrosis, while hepatic overexpression of Runx2 via HBAAV-Runx2 or VA-Lip-Runx2 injection exacerbated CCl4-induced liver fibrosis. In vitro analysis demonstrated that Runx2 promoted HSC activation and proliferation, whereas Runx2 knockdown in HSC suppressed these effects. RNA-seq and Runx2 ChIP-seq analysis demonstrated that Runx2 could promote integrin alpha-V (Itgav) expression by binding to its promoter. Blockade of Itgav attenuated Runx2-induced HSC activation and liver fibrosis. Additionally, we found that cytokines (TGF-beta 1, PDGF, EGF) promote the expression and nuclear translocation of Runx2 through protein kinase A (PKA) in HSC. Conclusions: Runx2 is critical for HSC activation via transcriptionally regulating Itgav expression during liver fibrosis, and may be a promising therapeutic target for liver fibrosis."

基金机构："Chongqing Science and Technology Commission Foundation [cstc2020jcyj-msxmX0045]; National Natural Science Foundation of China [82070626, 82100656]; China Postdoctoral Science Foundation [2022M710563]; Science and Technology Joint Medical Foundation of Chongqing, China [2020FYYX008]; Chongqing Municipal Education Commission Foundation [KJQN202200405]; First Affiliated Hospital of Chongqing Medical University foundation [XKTS102]"

基金资助正文："Chongqing Science and Technology Commission Foundation, Grant/Award Number: cstc2020jcyj-msxmX0045; National Natural Science Foundation of China, Grant/Award Numbers: 82070626, 82100656; China Postdoctoral Science Foundation, Grant/Award Number: 2022M710563; Science and Technology Joint Medical Foundation of Chongqing, China, Grant/Award Number: 2020FYYX008; Chongqing Municipal Education Commission Foundation, Grant/Award Number: KJQN202200405; First Affiliated Hospital of Chongqing Medical University foundation, Grant/Award Number: XKTS102"