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A Dual Role of HGF-ERK Signaling in IL6/HGF-induced Hepatocyte Proliferation

文献类型：期刊论文

作者Zhang, Jingwei1,2,3; Wang, Shitong2,3; Yu, Jiani1,2,3; Li, Bing2,3,4; Wang, Shun2,3; Suo, Na2; Guo, Ren2,5; Xie, Xin1,2,3,4,5
刊名CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
出版日期2025
卷号19期号:9页码:17
关键词Hepatocyte HGF IL6 Liver Parenchymal Cell Pro-liferation TGF-beta
ISSN号2352-345X
DOI10.1016/j.jcmgh.2025.101538
英文摘要BACKGROUND & AIMS: Primary hepatocytes are difficult to expand in vitro. Hepatocyte growth factor (HGF) and epidermal growth factor (EGF) have long been used to maintain primary hepatocytes in vitro but with limited growth promotion effect. Previously, we reported that the combination of interleukin 6 (IL6) with HGF and EGF (or the combination of IL6 with either of these growth factors) could support almost infinite growth of hepatocytes. However, the downstream pathways of these growth factors in hepatocyte proliferation remain elusive. METHODS: Transcriptome analysis was carried out to analyze the activation of pathways under various culture condition. Pathway inhibitors were used in cell culture and a hepatectomy mouse model to study the function of different pathways in hepatocyte growth and liver regeneration. RESULTS: We surprisingly discovered, that under growth condition, the transforming growth factor ,6 (TGF,6) pathway, which is typically linked to growth inhibition, is activated. TGF,6 activation is mainly induced by HGF via mitogen-activated protein kinase (MAPK)-extracellular regulated protein kinase (ERK) signaling; blocking the TGF,6 pathway significantly enhances H6 (HGF and IL6)-induced hepatocyte expansion in vitro. However, blocking the MAPK-ERK signaling almost completely blocks H6-induced cell growth, indicating a dual effect of the ERK pathway. Further study demonstrates that the HGF-ERK pathway could also upregulate the protein level of YAP and the downstream genes associated with the Hippo-YAP signaling pathway, exerting a positive effect in hepatocyte proliferation. In a mouse partial hepatectomy model, blockade of the activated TGF,6 signaling also significantly promotes liver regeneration in vivo. CONCLUSIONS: We report a dual role of HGF-ERK signaling in hepatocyte culture. By blocking the growth-inhibiting TGF6 pathway, we could further promote H6-induced hepatocyte proliferation. (Cell Mol Gastroenterol Hepatol 2025;19:101538; https://doi.org/10.1016/j.jcmgh.2025.101538)
WOS关键词GROWTH-FACTOR-BETA ; CELL-CYCLE ARREST ; PARTIAL-HEPATECTOMY ; LIVER-REGENERATION ; INHIBITION ; PATHWAY ; PROTEIN ; SUPPRESSION ; ACTIVATION ; MIGRATION
资助项目Ministry of Science and Technology of China[2022YFA1104700] ; Youth Innovation Promotion Association of CAS[2022280] ; National Natural Science Foundation of China[82121005] ; National Natural Science Foundation of China[32000504] ; Fundamental Research Projects of Science & Technology Innovation and development Plan in Yantai City[2023JCYJ063] ; Shanghai Municipal Committee of Science and Technology[23J11900100] ; Taishan Scholars Program
WOS研究方向Gastroenterology & Hepatology
语种英语
WOS记录号WOS:001521252700001
出版者ELSEVIER INC
源URL[http://119.78.100.183/handle/2S10ELR8/321024]  
专题国家级研究中心_原创新药研究全国重点实验室
通讯作者Guo, Ren; Xie, Xin
作者单位1.Shanghai Tech Univ, Sch Life Sci & Technol, Shanghai, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, Natl Ctr Drug Screening, State Key Lab Drug Res, Shanghai, Peoples R China
3.Univ Chinese Acad Sci, Beijing, Peoples R China
4.Univ Chinese Acad Sci, Hangzhou Inst Adv Study, Sch Pharmaceut Sci & Technol, Hangzhou, Peoples R China
5.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Zhang, Jingwei,Wang, Shitong,Yu, Jiani,et al. A Dual Role of HGF-ERK Signaling in IL6/HGF-induced Hepatocyte Proliferation[J]. CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY,2025,19(9):17.
APA Zhang, Jingwei.,Wang, Shitong.,Yu, Jiani.,Li, Bing.,Wang, Shun.,...&Xie, Xin.(2025).A Dual Role of HGF-ERK Signaling in IL6/HGF-induced Hepatocyte Proliferation.CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY,19(9),17.
MLA Zhang, Jingwei,et al."A Dual Role of HGF-ERK Signaling in IL6/HGF-induced Hepatocyte Proliferation".CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY 19.9(2025):17.

入库方式： OAI收割

来源：上海药物研究所

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