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Journal of Integrative Medicine ›› 2023, Vol. 21 ›› Issue (1): 47-61.doi: 10.1016/j.joim.2022.11.002

• Original Experimental Research • Previous Articles     Next Articles

Huangqi Decoction, a compound Chinese herbal medicine, inhibits the proliferation and activation of hepatic stellate cells by regulating the long noncoding RNA-C18orf26-1/microRNA-663a/transforming growth factor-β axis

Ben-sheng Donga, Fu-qun Liub,c, Wen-na Yangb,c, Xiao-dong Lid, Miao-juan Shia, Mao-rong Lia, Xiu-li Yane, Hui Zhanga   

  1. a. Traditional Chinese Medicine Epigenomics Research Center, Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
    b. Department of Rheumatology and Immunology, Nanjing Lishui District Hospital of Traditional Chinese Medicine, Nanjing 211299, Jiangsu Province, China
    c. Department of Rheumatology and Immunology, Yangzhou University Medical College, Yangzhou 225000, Jiangsu Province, China
    d. Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kita-gun, Kagawa 761-0793, Japan
    e. Department of Gastroenterology, Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China
  • Online:2023-01-19
  • Contact: Hui Zhang: zhanghuiman@126.com

Objective

Huangqi Decoction (HQD), a classical traditional Chinese medicine formula, has been used as a valid treatment for alleviating liver fibrosis; however, the underlying molecular mechanism is still unknown. Although our previous studies showed that microRNA-663a (miR-663a) suppresses the proliferation and activation of hepatic stellate cells (HSCs) and the transforming growth factor-β/small mothers against decapentaplegic (TGF-β/Smad) pathway, whether long noncoding RNAs (lncRNAs) are involved in HSC activation via the miR-663a/TGF-β/Smad signaling pathway has not yet reported. The present study aimed to investigate the roles of lncRNA lnc-C18orf26-1 in the activation of HSCs and the mechanism by which HQD inhibits hepatic fibrosis.

Methods

The expression levels of lnc-C18orf26-1, miR-663a and related genes were measured by quantitative reverse transcription-polymerase chain reaction. HSCs were transfected with the miR-663a mimic or inhibitor and lnc-C18orf26-1 small interfering RNAs. The water-soluble tetrazolium salt-1 assay was used to assess the proliferation rate of HSCs. Changes in lncRNA expression were evaluated in miR-663a-overexpressing HSCs by using microarray to identify miR-663a-regulated lncRNAs. RNA hybrid was used to predict the potential miR-663a binding sites on lncRNAs. Luciferase reporter assays further confirmed the interaction between miR-663a and the lncRNA. The expression levels of collagen α-2(I) chain (COL1A2), α-smooth muscle actin (α-SMA) and TGF-β/Smad signaling pathway-related proteins were determined using Western blotting.

Results

Lnc-C18orf26-1 was upregulated in TGF-β1-activated HSCs and competitively bound to miR-663a. Knockdown of lnc-C18orf26-1 inhibited HSC proliferation and activation, downregulated TGF-β1-stimulated α-SMA and COL1A2 expression, and inhibited the TGF-β1/Smad signaling pathway. HQD suppressed the proliferation and activation of HSCs. HQD increased miR-663a expression and decreased lnc-C18orf26-1 expression in HSCs. Further studies showed that HQD inhibited the expression of COL1A2, α-SMA, TGF-β1, TGF-β type I receptor (TGF-βRI) and phosphorylated Smad2 (p-Smad2) in HSCs, and these effects were reversed by miR-663a inhibitor treatment.

Conclusion

Our study identified lnc-C18orf26-1 and miR-663a as promising therapeutic targets for hepatic fibrosis. HQD inhibits HSC proliferation and activation at least partially by regulating the lnc-C18orf26-1/miR-663a/TGF-β1/TGF-βRI/p-Smad2 axis.

Key words: Long noncoding RNA-C18orf26-1, MicroRNA-663a, Transforming growth factor-β, Hepatic stellate cells, Huangqi Decoction

[1] Shui-jie Shen, Yong-hong Zhang, Xiao-xia Gu, Shui-ju Jiang, Ling-jun Xu. Yangfei Kongliu Formula, a compound Chinese herbal medicine, combined with cisplatin, inhibits growth of lung cancer cells through transforming growth factor-β1 signaling pathway. Journal of Integrative Medicine, 2017, 15(3): 242-251.
[2] Ya-fang Song, Zhi-gang Lv, Lie-ruing Xu. Salvianolic acid B inhibits ERK signal transduction pathway activated by transforming growth factor-β1 in rat hepatic stellate cells. Journal of Chinese Integrative Medicine, 2012, 10(4): 454-461.
[3] Lei Wang, Guang Ji, Wei Zhang, Lian-jun Xing, Pei-yong Zheng. Hepatic stellate cell apoptosis and mitochondrion. Journal of Chinese Integrative Medicine, 2005, 3(2): 144-148.
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