Ginsenoside CK Inhibits Hypoxia-Induced Epithelial–Mesenchymal Transformation through the HIF-1α/NF-κB Feedback Pathway in Hepatocellular Carcinoma
Hepatocellular carcinoma (HCC) is a kind of malignant tumor with high morbidity and mortality rates worldwide. Epithelial–mesenchymal transformation (EMT) is crucial for HCC progression and prognosis. Characteristics of the tumor microenvironment, such as hypoxia, and excessive activation of the NF-...
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MDPI AG
2021-05-01
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| Online Access: | https://www.mdpi.com/2304-8158/10/6/1195 |
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| author | Jingjing Zhang Xiaoxuan Ma Daidi Fan |
| author_facet | Jingjing Zhang Xiaoxuan Ma Daidi Fan |
| author_sort | Jingjing Zhang |
| collection | DOAJ |
| description | Hepatocellular carcinoma (HCC) is a kind of malignant tumor with high morbidity and mortality rates worldwide. Epithelial–mesenchymal transformation (EMT) is crucial for HCC progression and prognosis. Characteristics of the tumor microenvironment, such as hypoxia, and excessive activation of the NF-κB signaling pathway have been identified as the key inducers of EMT in HCC. In our study, we verified the crosstalk between HIF-1α signaling and NF-κB pathway and their effects on EMT in HCC cells. The results show that CoCl<sub>2</sub>-induced hypoxia could promote IκB phosphorylation to activate NF-κB signaling and vice versa. Moreover, we found that ginsenoside CK, a metabolite of protopanaxadiol saponins, could inhibit the proliferation and colony formation of different HCC cell lines. Furthermore, ginsenoside CK could impair the metastatic potential of HCC cell lines under hypoxic conditions. Mechanistically, ginsenoside CK suppressed HIF-1α/NF-κB signaling and expression level of EMT-related proteins and cytokines in hypoxia-induced or TNFα-stimulated HCC cell lines. An in vivo study revealed that the oral delivery of ginsenoside CK could inhibit the growth of xenograft tumors and block HIF-1α and NF-κB signaling as well as EMT marker expression. Our study suggests that ginsenoside CK is a potential therapy for HCC patients that functions by targeting the HIF-1α/NF-κB crosstalk. |
| first_indexed | 2024-03-10T11:02:56Z |
| format | Article |
| id | doaj.art-ead1d4933c704064b61322ef44fbde6c |
| institution | Directory Open Access Journal |
| issn | 2304-8158 |
| language | English |
| last_indexed | 2024-03-10T11:02:56Z |
| publishDate | 2021-05-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Foods |
| spelling | doaj.art-ead1d4933c704064b61322ef44fbde6c2023-11-21T21:22:56ZengMDPI AGFoods2304-81582021-05-01106119510.3390/foods10061195Ginsenoside CK Inhibits Hypoxia-Induced Epithelial–Mesenchymal Transformation through the HIF-1α/NF-κB Feedback Pathway in Hepatocellular CarcinomaJingjing Zhang0Xiaoxuan Ma1Daidi Fan2Shaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi’an 710069, ChinaShaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi’an 710069, ChinaShaanxi Key Laboratory of Degradable Biomedical Materials, School of Chemical Engineering, Northwest University, 229 Taibai North Road, Xi’an 710069, ChinaHepatocellular carcinoma (HCC) is a kind of malignant tumor with high morbidity and mortality rates worldwide. Epithelial–mesenchymal transformation (EMT) is crucial for HCC progression and prognosis. Characteristics of the tumor microenvironment, such as hypoxia, and excessive activation of the NF-κB signaling pathway have been identified as the key inducers of EMT in HCC. In our study, we verified the crosstalk between HIF-1α signaling and NF-κB pathway and their effects on EMT in HCC cells. The results show that CoCl<sub>2</sub>-induced hypoxia could promote IκB phosphorylation to activate NF-κB signaling and vice versa. Moreover, we found that ginsenoside CK, a metabolite of protopanaxadiol saponins, could inhibit the proliferation and colony formation of different HCC cell lines. Furthermore, ginsenoside CK could impair the metastatic potential of HCC cell lines under hypoxic conditions. Mechanistically, ginsenoside CK suppressed HIF-1α/NF-κB signaling and expression level of EMT-related proteins and cytokines in hypoxia-induced or TNFα-stimulated HCC cell lines. An in vivo study revealed that the oral delivery of ginsenoside CK could inhibit the growth of xenograft tumors and block HIF-1α and NF-κB signaling as well as EMT marker expression. Our study suggests that ginsenoside CK is a potential therapy for HCC patients that functions by targeting the HIF-1α/NF-κB crosstalk.https://www.mdpi.com/2304-8158/10/6/1195hepatocellular carcinomaepithelial–mesenchymal transformationhypoxiaNF-κB signalingginsenoside CK |
| spellingShingle | Jingjing Zhang Xiaoxuan Ma Daidi Fan Ginsenoside CK Inhibits Hypoxia-Induced Epithelial–Mesenchymal Transformation through the HIF-1α/NF-κB Feedback Pathway in Hepatocellular Carcinoma Foods hepatocellular carcinoma epithelial–mesenchymal transformation hypoxia NF-κB signaling ginsenoside CK |
| title | Ginsenoside CK Inhibits Hypoxia-Induced Epithelial–Mesenchymal Transformation through the HIF-1α/NF-κB Feedback Pathway in Hepatocellular Carcinoma |
| title_full | Ginsenoside CK Inhibits Hypoxia-Induced Epithelial–Mesenchymal Transformation through the HIF-1α/NF-κB Feedback Pathway in Hepatocellular Carcinoma |
| title_fullStr | Ginsenoside CK Inhibits Hypoxia-Induced Epithelial–Mesenchymal Transformation through the HIF-1α/NF-κB Feedback Pathway in Hepatocellular Carcinoma |
| title_full_unstemmed | Ginsenoside CK Inhibits Hypoxia-Induced Epithelial–Mesenchymal Transformation through the HIF-1α/NF-κB Feedback Pathway in Hepatocellular Carcinoma |
| title_short | Ginsenoside CK Inhibits Hypoxia-Induced Epithelial–Mesenchymal Transformation through the HIF-1α/NF-κB Feedback Pathway in Hepatocellular Carcinoma |
| title_sort | ginsenoside ck inhibits hypoxia induced epithelial mesenchymal transformation through the hif 1α nf κb feedback pathway in hepatocellular carcinoma |
| topic | hepatocellular carcinoma epithelial–mesenchymal transformation hypoxia NF-κB signaling ginsenoside CK |
| url | https://www.mdpi.com/2304-8158/10/6/1195 |
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