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Published on: March 30, 2019
Andrographolide anti-proliferation and metastasis of hepatocellular carcinoma through LncRNA MIR22HG regulation
Yan Luo1, Jiaxuan Hu1, Yue Jiao2
1Key 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.
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.
Insights
Andrographolide (Andro) inhibits hepatocellular carcinoma (HCC) cell proliferation and metastasis by regulating MIR22HG and HMGB1/MMP-9 pathways. This natural compound offers a new therapeutic strategy for HCC treatment.
Area of Science:
- Hepatology
- Molecular Biology
- Pharmacology
Background:
- Hepatocellular carcinoma (HCC) treatment remains a significant clinical challenge.
- Andrographolide (Andro) exhibits anti-proliferative effects on HCC, but its mechanisms and anti-metastatic potential are largely unknown.
- Elucidating Andro's molecular targets is crucial for developing novel HCC therapies.
Purpose of the Study:
- To investigate the inhibitory effects of Andro on HCC cell proliferation and metastasis.
- To elucidate the underlying molecular mechanisms, including key signaling pathways and regulatory molecules.
- To evaluate Andro's therapeutic potential in preclinical HCC models.
Main Methods:
- In vitro studies using SK-Hep-1 HCC cells to assess proliferation, apoptosis, and invasion.
- In vivo studies using tumor-bearing nude mice to evaluate tumor growth inhibition.
- Molecular analyses including gene/protein expression (MIR22HG, BCL-2, Caspase 9/7/3, HMGB1, MMP-9), miRNA profiling (miR-22-3p), and gene knockdown/overexpression experiments (MIR22HG, HuR, HMGB1).
Main Results:
- Andro significantly reduced HCC cell survival, tumor weight, and volume in vivo.
- Andro induced apoptosis by upregulating MIR22HG and Cleaved Caspase 9/7/3, and downregulating BCL-2.
- Andro inhibited HCC cell invasion and lung metastasis by upregulating miR-22-3p and downregulating HMGB1 and MMP-9, mediated through MIR22HG-HuR/BCL-2 and MIR22HG/HMGB1 pathways.
Conclusions:
- Andrographolide effectively inhibits hepatocellular carcinoma proliferation and metastasis through modulation of MIR22HG-HuR/BCL-2 and MIR22HG/HMGB1 signaling pathways.
- This study provides a mechanistic basis for Andro's anti-cancer effects and highlights its potential as a therapeutic agent for HCC.
- Andro is identified as a novel natural product capable of positively regulating MIR22HG, a molecule with significant biological functions in HCC.
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