Abstract
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 CoCl2-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.
Highlights
To confirm the expression of hypoxia inducible factor-1α (HIF-1α) in tumors, we searched and analyzed the data in the GEPIA database and found that HIF-1α was more highly expressed in liver hepatocellular carcinoma (LIHC) (Figure 1A), glioblastoma multiforme (GBM) (Figure 1B), pancreatic adenocarcinoma (PAAD) (Figure 1C) and acute myeloid leukemia (LAML) (Figure 1D)
The HIF-1α expression level was related to the length of overall survival (Figure 1I) and disease-free survival (Figure 1J) of Hepatocellular carcinoma (HCC) patients, where high HIF-1α expression corresponded to poor survival outcomes
We observed a positive association between HIF-1α and the Epithelial–mesenchymal transformation (EMT)-related cytokine Snail (R = 0.34, p = 1.1 × 10−11 ; Figure 1E), HIF-1α and the NF-κB target gene ICAM-1 (R = 0.47, p = 0; Figure 1F), HIF-1α and c-Myc (R = 0.26, p = 6.4 × 10−7 ; Figure 1G), and HIF-1α and VEGFA
Summary
Hepatocellular carcinoma (HCC) is a malignant tumor that accounts for 75–85% of the total cases of primary liver cancer [1] and is one of the leading causes of cancer-related death worldwide [2]. Early-stage HCC can achieve a relatively high cure rate through surgical resection, liver transplantation, radiofrequency ablation and other treatment methods; most patients are diagnosed with advanced hepatocarcinoma, which has poor treatment efficacy and survival quality. There are multiple factors affecting the therapeutic efficacy for HCC, including epithelial–mesenchymal transformation (EMT), which plays a crucial part in HCC progression and is characterized by the reducing expression of E-cadherin (epithelial marker) and increase in N-cadherin (mesenchymal marker) [4]. Through EMT, tumor cells have increased migration and invasion abilities and prevent themselves from undergoing apoptosis and escape surveillance of the host immune system and drug therapy [5]
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