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Andrographolide anti-proliferation and metastasis of hepatocellular carcinoma through LncRNA MIR22HG regulation

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Abstract

Hepatocellular carcinoma (HCC) treatment is a major challenge. Although andrographolide (Andro) has an anti-proliferation effect on HCC, its underlying mechanism is not yet elucidated, and whether Andro can inhibit HCC metastasis has not been reported. The present study aimed to clarify whether Andro inhibits SK-Hep-1 cell proliferation and HCC metastasis, and the mechanisms. The results showed that Andro significantly reduced the survival of HCC cells and tumor weight and volume in tumor-bearing nude mice. Andro also triggered apoptosis of HCC cells and upregulated MIR22HG, Cleaved Caspase 9/7/3 expression levels, and downregulated BCL-2 mRNA, BCL-2 expression levels. Knockdown of MIR22HG or overexpression of HuR attenuated the effects of Andro on the signal transduction of mitochondrial apoptotic pathway and proliferation ability in HCC cells. Moreover, Andro significantly reduced the invasive ability of the cells and the level of HCC cell lung metastasis, upregulated miR-22-3p expression level and downregulated HMGB1 and MMP-9 expression levels. MIR22HG or miR-22-3p knockdown attenuated the effects of Andro on the signaling of HMGB1/MMP-9 pathway and invasive ability in HCC cells, while the overexpression of HMGB1 attenuated the inhibitory effects of Andro on the MMP-9 expression level and invasive ability in HCC cells. Thus, the regulation of MIR22HG-HuR/BCL-2 and MIR22HG/HMGB1 signaling pathways is involved in the anti-HCC proliferation and metastasis effects of Andro. This study provided a new pharmacological basis for Andro in HCC treatment and, for the first time, identified a natural product molecule capable of positively regulating MIR22HG, which has a robust biological function.

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Abbreviations

Andro:

Andrographolide

HCC:

Hepatocellular carcinoma

CCK-8:

Cell counting kit-8

LDH:

Lactate dehydrogenase

EdU:

5-Ethynyl-20-deoxyuridine

PI:

Propidium iodide

TUNEL:

Terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling

MMP:

Matrix metalloproteinase

JC-1:

5,5′,6,6′-Tetrachloro-1,1′,3,3′-tetraethylbenzimidazolylcarbocyanine iodide

LncRNAs:

Long non-coding RNAs

BCL-2:

B-cell leukemia/lymphoma 2

MIR22HG:

Human miR-22 host gene

HuR:

Human antigen R

ALT:

Glutamic-pyruvic transaminase

AST:

Glutamic oxaloacetic transaminase

HMGB1:

High-mobility group protein B1

BUN:

Blood urea nitrogen

CREA:

Creatinine

Cyt C:

Cytochrome C

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Funding

This study was supported by National Natural Science Foundation of China (No. 82260793); China Postdoctoral Science Foundation funded project (No. 2020M680834); Jiangxi Provincial Natural Science Foundation (No. 20212BAB216002); The Key R & D Project of Ganzhou Science and Technology Plan Project (2022B-SF8897); The Start-up Fund of Gannan Medical University (No. QD201821); The Science and Technology Project of the Education Department of Jiangxi Province (No. GJJ211517).

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Author notes

  1. Yan Luo, Jiaxuan Hu, and Yue Jiao contributed equally.

Authors and Affiliations

  1. Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Key Laboratory of Biomaterials and Biofabrication in Tissue Engineering of Jiangxi Province, School of Pharmacy, Scientific Research Center, Gannan Medical University, Ganzhou, 341000, China

    Yan Luo, Jiaxuan Hu, Dan Miao, Yunlei Song, Wenjing Yan & Yumao Jiang

  2. China Academy of Chinese Medical Sciences, Beijing, 100700, China

    Yue Jiao, Liwei Liu & Yumao Jiang

  3. The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China

    Yi Li

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  1. Yan Luo
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Contributions

Conceived and designed the experiments: YJ, YL. Performed the experiments: YL, JH, YJ. Analyzed the data: JH, DM, YS, WY. Contributed reagents/materials/analysis tools: YJ, YL. Wrote and revised the paper: YJ, YL.

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Correspondence to Yi Li or Yumao Jiang.

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Luo, Y., Hu, J., Jiao, Y. et al. Andrographolide anti-proliferation and metastasis of hepatocellular carcinoma through LncRNA MIR22HG regulation. J Nat Med 78, 123–145 (2024). https://doi.org/10.1007/s11418-023-01752-4

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