中文｜English
ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R
Volume 40 Issue 6
Jun.  2024
Turn off MathJax
Article Contents
Article Navigation >  Journal of Clinical Hepatology  > 2024  >  40(6): 1142-1148

Effect of oxaliplatin on the activation of hepatic stellate cells and its mechanism

DOI: 10.12449/JCH240612
  • 1.

    Department of Geriatric Gastroenterology，Hebei General Hospital，Shijiazhuang 050000，China

  • 2.

    Department of Gastroenterology，Shijiazhuang People’s Hospital，Shijiazhuang 050011，China

  • 3.

    Department of Ophthalmology，Hebei Medical University Forth Hospital，Shijiazhuang 050011，China

  • 4.

    Department of Gastroenterology，The Second Hospital of Hebei Medical University，Shijiazhuang 050000，China

Research funding:

Medical Science Research Project of Hebei Province in 2023 (20230019)

More Information
  • Corresponding author: WANG Yuzhen， wyzhen211@126.com （ORCID： 0009-0001-4437-4616）
  • Received Date: 2023-09-06
  • Accepted Date: 2023-10-26
  • Published Date: 2024-06-25
    Abstract
  •   Objective  To investigate the effect of oxaliplatin on the activation of hepatic stellate cells （HSCs）， as well as the association of oxaliplatin with microRNA-30a-5p and autophagy.  Methods  HSC-LX2 cells were cultured and divided into groups according to the following three protocols： control group， PDGF treatment group， oxaliplatin treatment group， oxaliplatin+PDGF treatment group； control group， microRNA-30a-5p transfection group， PDGF treatment group， microRNA-30a-5p transfection+PDGF treatment group； control group， 3-MA group， microRNA-30a-5p inhibitor group， microRNA-30a-5p inhibitor+3-MA group. Western Blot was used to measure the expression of HSC activation-related proteins （Collagen-I and alpha-smooth muscle actin ［α- SMA］） and HSC autophagy-related proteins （Beclin-1， P62， and LC3B）； LysoTracker staining and immunofluorescence assay were used to measure the expression of LC3B autophagosomes； RT-PCR was used to measure the expression level of microRNA-30a-5p； bioinformatics techniques were used to predict the potential targets of microRNA-30a-5p in HSCs. The independent-samples t test was used for comparison of normally distributed continuous data between two groups； a one-way analysis of variance was used for comparison between multiple groups， and the least significant difference t-test was used for further comparison between two groups.  Results  After the cells were treated with oxaliplatin， RT-PCR results showed that the oxaliplatin treatment group had a significantly higher expression level of microRNA-30a-5p than the control group （P<0.01）； Western Blot showed that the oxaliplatin treatment group had significant reductions in the expression levels of the HSC activation-related proteins α-SMA and Collagen-‍Ⅰ and the autophagy-related proteins Beclin 1 and LC3BⅡ/Ⅰ （all P<0.001）； immunofluorescence assay showed that the oxaliplatin treatment group had a significantly lower number of autophagosomes than the control group （P<0.05）. After HSC-LX2 cells were transfected with microRNA-30a-5p mimic， compared with the control group， the microRNA-30a-5p mimic group had significant reductions in the expression levels of the autophagy-related proteins Beclin 1 and LC3BⅡ/Ⅰ （P<0.05） and the HSC activation-related protein Collagen-‍‍Ⅰ （P<0.001）； after HSC-LX2 cells were transfected with microRNA-30a-5p inhibitor， Western Blot showed that compared with the control group， the microRNA-30a-5p inhibitor group had significant increases in the expression levels of the HSC activation-related proteins Collagen-‍Ⅰ and α-SMA and the autophagy-related protein Beclin 1 （t=2.41， 2.32， and 4.57， all P<0.05）. Western Blot showed that compared with the control group， the microRNA-30a-5p inhibitor group had significant increases in the expression levels of the HSC autophagy-related protein Beclin 1 and the HSC activation-related protein α-SMA （both P<0.05）， and after the treatment with the autophagy inhibitor 3-MA， there were no significant differences in the expression of these proteins between the two groups （P>0.05）. The bioinformatics analysis using TargetScan， PicTar， and miRanda databases showed that the autophagy-related protein Beclin-1 might be a potential target of miRNA-30a-5p.  Conclusion  Oxaliplatin can inhibit the activation of HSCs by upregulating the expression of microRNA-30a-5p， which provides new ideas and a new target for the treatment of liver fibrosis.

     

    • FullText(HTML)
  • loading
    • References(27)
  • [1]
    WEISKIRCHEN R, TACKE F. Liver fibrosis: From pathogenesis to novel therapies[J]. Dig Dis, 2016, 34( 4): 410- 422. DOI: 10.1159/000444556.
    [2]
    AYDIN MM, AKCALI KC. Liver fibrosis[J]. Turk J Gastroenterol, 2018, 29( 1): 14- 21. DOI: 10.5152/tjg.2018.17330.
    [3]
    BANSAL MB, CHAMROONKUL N. Antifibrotics in liver disease: Are we getting closer to clinical use?[J]. Hepatol Int, 2019, 13( 1): 25- 39. DOI: 10.1007/s12072-018-9897-3.
    [4]
    History GEERTS A., heterogeneity, biology developmental, and functions of quiescent hepatic stellate cells[J]. Semin Liver Dis, 2001, 21( 3): 311- 335. DOI: 10.1055/s-2001-17550.
    [5]
    ZHANG CY, YUAN WG, HE P, et al. Liver fibrosis and hepatic stellate cells: Etiology, pathological hallmarks and therapeutic targets[J]. World J Gastroenterol, 2016, 22( 48): 10512- 10522. DOI: 10.3748/wjg.v22.i48.10512.
    [6]
    YAMAGUCHI K, YANG L, MCCALL S, et al. Diacylglycerol acyltranferase 1 anti-sense oligonucleotides reduce hepatic fibrosis in mice with nonalcoholic steatohepatitis[J]. Hepatology, 2008, 47( 2): 625- 635. DOI: 10.1002/hep.21988.
    [7]
    HERNÁNDEZ-GEA V, GHIASSI-NEJAD Z, ROZENFELD R, et al. Autophagy releases lipid that promotes fibrogenesis by activated hepatic stellate cells in mice and in human tissues[J]. Gastroenterology, 2012, 142( 4): 938- 946. DOI: 10.1053/j.gastro.2011.12.044.
    [8]
    SAITO T, KUMA A, SUGIURA Y, et al. Autophagy regulates lipid metabolism through selective turnover of NCoR1[J]. Nat Commun, 2019, 10( 1): 1567. DOI: 10.1038/s41467-019-08829-3.
    [9]
    TSUKAMOTO H. Cytokine regulation of hepatic stellate cells in liver fibrosis[J]. Alcohol Clin Exp Res, 1999, 23( 5): 911- 916.
    [10]
    LI JT, LIAO ZX, PING J, et al. Molecular mechanism of hepatic stellate cell activation and antifibrotic therapeutic strategies[J]. J Gastroenterol, 2008, 43( 6): 419- 428. DOI: 10.1007/s00535-008-2180-y.
    [11]
    KITANO M, BLOOMSTON PM. Hepatic stellate cells and microRNAs in pathogenesis of liver fibrosis[J]. J Clin Med, 2016, 5( 3): 38. DOI: 10.3390/jcm5030038.
    [12]
    GRIMSON A, FARH KKH, JOHNSTON WK, et al. MicroRNA targeting specificity in mammals: Determinants beyond seed pairing[J]. Mol Cell, 2007, 27( 1): 91- 105. DOI: 10.1016/j.molcel.2007.06.017.
    [13]
    IORIO MV, CROCE CM. Causes and consequences of microRNA dysregulation[J]. Cancer J, 2012, 18( 3): 215- 222. DOI: 10.1097/PPO.0b013e318250c001.
    [14]
    LU RQ, ZHAO G, YANG YL, et al. Long noncoding RNA HOTAIRM1 inhibits cell progression by regulating miR-17-5p/PTEN axis in gastric cancer[J]. J Cell Biochem, 2019, 120( 4): 4952- 4965. DOI: 10.1002/jcb.27770.
    [15]
    FENG MH, LI JW, SUN HT, et al. Sulforaphane inhibits the activation of hepatic stellate cell by miRNA-423-5p targeting suppressor of fused[J]. Hum Cell, 2019, 32( 4): 403- 410. DOI: 10.1007/s13577-019-00264-2.
    [16]
    YU XX, RUAN Y, SHEN T, et al. Dexrazoxane protects cardiomyocyte from doxorubicin-induced apoptosis by modulating miR-17-5p[J]. Biomed Res Int, 2020, 2020: 5107193. DOI: 10.1155/2020/5107193.
    [17]
    HAZARI Y, BRAVO-SAN PEDRO JM, HETZ C, et al. Autophagy in hepatic adaptation to stress[J]. J Hepatol, 2020, 72( 1): 183- 196. DOI: 10.1016/j.jhep.2019.08.026.
    [18]
    APPS MG, CHOI EHY, WHEATE NJ. The state-of-play and future of platinum drugs[J]. Endocr Relat Cancer, 2015, 22( 4): R219- R233. DOI: 10.1530/ERC-15-0237.
    [19]
    TAN SF, SHI HJ, BA MC, et al. MiR-409-3p sensitizes colon cancer cells to oxaliplatin by inhibiting Beclin-1-mediated autophagy[J]. Int J Mol Med, 2016, 37( 4): 1030- 1038. DOI: 10.3892/ijmm.2016.2492.
    [20]
    ZHU H, WU H, LIU XP, et al. Regulation of autophagy by a beclin 1-targeted microRNA, miR-30a, in cancer cells[J]. Autophagy, 2009, 5( 6): 816- 823. DOI: 10.4161/auto.9064.
    [21]
    TSOCHATZIS EA, BOSCH J, BURROUGHS AK. Liver cirrhosis[J]. Lancet, 2014, 383( 9930): 1749- 1761. DOI: 10.1016/S0140-6736(14)60121-5.
    [22]
    POPOV Y, SCHUPPAN D. Targeting liver fibrosis: Strategies for development and validation of antifibrotic therapies[J]. Hepatology, 2009, 50( 4): 1294- 1306. DOI: 10.1002/hep.23123.
    [23]
    FRIEDMAN SL. Hepatic stellate cells: Protean, multifunctional, and enigmatic cells of the liver[J]. Physiol Rev, 2008, 88( 1): 125- 172. DOI: 10.1152/physrev.00013.2007.
    [24]
    KISSELEVA T, BRENNER DA. Role of hepatic stellate cells in fibrogenesis and the reversal of fibrosis[J]. J Gastroenterol Hepatol, 2007, 22( Suppl 1): S73- S78. DOI: 10.1111/j.1440-1746.2006.04658.x.
    [25]
    WANG J, CHU ESH, CHEN HY, et al. MicroRNA-29b prevents liver fibrosis by attenuating hepatic stellate cell activation and inducing apoptosis through targeting PI3K/AKT pathway[J]. Oncotarget, 2015, 6( 9): 7325- 7338. DOI: 10.18632/oncotarget.2621.
    [26]
    OKADA H, HONDA M, CAMPBELL JS, et al. Inhibition of microRNA-214 ameliorates hepatic fibrosis and tumor incidence in platelet-derived growth factor C transgenic mice[J]. Cancer Sci, 2015, 106( 9): 1143- 1152. DOI: 10.1111/cas.12730.
    [27]
    KLINKHAMMER BM, FLOEGE J, BOOR P. PDGF in organ fibrosis[J]. Mol Aspects Med, 2018, 62: 44- 62. DOI: 10.1016/j.mam.2017.11.008.
    • Relative Articles
    • Supplements(0)
    • Cited By
  • 加载中

Catalog

    通讯作者: 陈斌, bchen63@163.com
    • 1. 

      沈阳化工大学材料科学与工程学院 沈阳 110142

    1. 本站搜索
    2. 百度学术搜索
    3. 万方数据库搜索
    4. CNKI搜索

    Figures(9)

    Get Citation
    PDF
    XML

    Article Metrics

    Article views (47) PDF downloads(11) Cited by()
    Proportional views
    Related
        

    The first journal specializing in hepatobiliary and pancreatic diseases in China

    Supervisor：Ministry of Education of the People's Republic of China

    Sponsor：Jilin University

    Academic Support: Chinese Society of Hepatology，Chinese Medical Association

    Address: 461 Xinjiang Road, Changchun

    Submit：0431-88782044

    Peer review：0431-88783542

    Email：lcgdb@vip.163.com

    About Journal

    Submission Guideline

    Journal Online

    Hepatobiliary College

    Guidelines

    YesterdayIP[]YesterdayPV[]TodayIP[]TodayPV[]Online[]

    Website Design © 2020 Editorial Board of Journal of Clinical Hepatology 吉ICP备10000617号-1 Supported by: Beijing Renhe Information Technology Co. Ltd  

    /

    DownLoad:  Full-Size Img  PowerPoint
    Return
    Return