Inhibitory effect of 6-paradol on the proliferation, migration, and invasion of intrahepatic cholangiocarcinoma cells and its mechanism

Zehao CHEN; Wenjie ZHU; Bingbing SHEN; Jianxin JIANG

doi:10.3969/j.issn.1001-5256.2022.04.022

Volume 38 Issue 4

Apr. 2022

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Inhibitory effect of 6-paradol on the proliferation, migration, and invasion of intrahepatic cholangiocarcinoma cells and its mechanism

DOI: 10.3969/j.issn.1001-5256.2022.04.022

Department of Hepatobiliary Surgery, Renmin Hospital of Wuhan University, Wuhan 430061, China

Research funding:

National Natural Science Foundation of China (81871965)

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Corresponding author: JIANG Jianixn, rm002979@whu.edu.cn(ORCID: 0000-0001-7939-9082)
Received Date: 2021-08-24
Published Date: 2022-04-20

Abstract

Abstract

Objective To investigate the effect of 6-paradol on the proliferation, migration, and invasion of human intrahepatic cholangiocarcinoma cells and its mechanism. Methods Human intrahepatic cholangiocarcinoma cell lines HCCC 9810 and HUCCT1 were treated with different concentrations of 6-paradol or an equal volume of DMSO (control group), and then CCK-8 assay, plate colony formation assay, wound healing assay, and Transwell assay were used to measure cell proliferation, migration, and invasion. The bioinformatics software Swiss Target Prediction was used to predict the protein targets of 6-paradol, and Western blot was used to measure the protein expression levels of STAT3, p-STAT3, SRC, p-mTOR, p21, Bcl-2, and p53; Drug Affinity Responsive Target Stability (DARTS) assay was used to investigate the interaction between 6-paradol and STAT3. After cholangiocarcinoma HCCC 9810 and HUCCT1 cells were transfected with STAT3 overexpression plasmid or sh-p21 plasmid, quantitative real-time PCR was used to measure the mRNA expression levels of STAT3 and p21, and Western blot was used to measure the protein expression levels of STAT3 and p21; CCK-8 assay, wound healing assay, and Transwell assay were used to measure cell proliferation, migration, and invasion. The t-test was used for comparison of data between two groups; an 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 Compared with the control group, the 6-paradol treatment groups had significant reductions in cell proliferation, migration, and invasion (P < 0.05). Compared with the control group, the 6-paradol treatment groups had significant reductions in the expression levels of STAT3 and p-STAT3 (all P < 0.05) and a significant increase in the expression level of p21 (all P < 0.05), while there were no significant changes in the expression levels of Bcl-2, SRC, and p-mTOR (all P > 0.05). In the 6-paradol treatment groups, the proportion of STAT3 hydrolyzed by protease was reduced by 48.66% and 45.33%, respectively (t=16.64 and 8.76, both P < 0.05); after transfection with STAT3 overexpression plasmid or p21-silencing plasmid in cholangiocarcinoma cells, there was a significant increase in the mRNA expression level of STAT3 (t_{HCCC 9810}=2.82, t_HUCCT1=5.60, both P < 0.05) and a significant reduction in the mRNA expression level of p21 (t_{HCCC 9810}=6.84, t_HUCCT1=3.91, both P < 0.05). CCK-8 assay showed that for HCCC 9810 and HUCCT1 cells treated with 6-paradol for 48 and 72 hours, the STAT3 overexpression group had a significantly higher proliferation rate than the single administration group, and the p21 silencing group also had a significantly higher proliferation rate than the single administration group (P < 0.05). The wound healing assay showed that the HCCC 9810 and HUCCT1 cells with STAT3 overexpression or p21 silencing had a significantly higher wound healing rate than the single administration group (all P < 0.05). Transwell assay showed that the HCCC 9810 and HUCCT1 cells with STAT3 overexpression or p21 silencing had significant increases in migration rate and invasion rate compared with the single administration group (all P < 0.05). Conclusion 6-Paradol inhibits the proliferation, migration, and invasion of cholangiocarcinoma cells by targeting the STAT3-p21 pathway.
- Intrahepatic Cholangiocarcinoma,
- STAT3 Transcription Factor,
- 6-Paradol,
- Cell Proliferation,
- Neoplasm Invasiveness

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Inhibitory effect of 6-paradol on the proliferation, migration, and invasion of intrahepatic cholangiocarcinoma cells and its mechanism

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Inhibitory effect of 6-paradol on the proliferation, migration, and invasion of intrahepatic cholangiocarcinoma cells and its mechanism

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