Suppression of Hepatocellular Carcinoma Progression through FOXM1 and EMT Inhibition via Hydroxygenkwanin-Induced miR-320a Expression.

Li-Fang Chou,Junn-Liang Chang,Chin-Chuan Chen,Yann-Lii Leu,Wan-Hua Yang,Chi-Yuan Chen,Tong-Hong Wang,Miaw-Jene Liou

doi:10.3390/biom10010020

Abstract

Daphne genkwa, a Chinese medicinal herb, is used frequently in Southeast Asian countries to treat diseases; the flavonoid hydroxygenkwanin (HGK) is extracted from its flower buds. The bioactivity of HGK, particularly as an anti-liver cancer agent, has not been explored. In this study, human hepatocellular carcinoma (HCC) cell lines and an animal xenograft model were employed to investigate both the activity of HGK against liver cancer and its cellular signaling mechanisms. HCC cells treated with HGK were subjected to cell function assays. Whole transcriptome sequencing was used to identify genes whose expression was influenced by HGK, and the flavonoid’s cancer suppression mechanisms were further investigated through gain- and loss-of-function assays. Finally, in vitro findings were tested in a mouse xenograft model. The data showed that HGK induced the expression of the microRNA miR-320a, which in turn inhibited the expression of the transcription factor ‘forkhead box protein M1’ (FOXM1) and downstream FOXM1-regulated proteins related to epithelial–mesenchymal transition, thereby leading to the suppression of liver cancer cell growth and invasion. Significant inhibition of tumor growth was also observed in HGK-treated mice. Hence, the present study demonstrated the activity of HGK against liver cancer and validated its potential use as a therapeutic agent.

Highlights

According to the World Health Organization statistics published in 2018, liver cancer is the seventh most common malignancy in the world and is the second leading cause of cancer-related death.Globally, approximately 780,000 people die from liver cancer every year [1]
No inhibitory effect was observed on the growth of human skin fibroblast cell line Human skin fibroblast (HFB) at the above concentrations (Figure 1B)
The efficacy of natural products against diseases has been shown in numerous studies, and has led to the use ofofcertain in studies, current and clinical

Summary

Introduction

According to the World Health Organization statistics published in 2018, liver cancer is the seventh most common malignancy in the world and is the second leading cause of cancer-related death. Approximately 780,000 people die from liver cancer every year [1]. In Africa and Asia, hepatitis B virus infection is the etiologic factor in approximately 60% of patients with liver cancer [6,7]. In addition to triggering the malignant transformation of liver cells during the progression of chronic hepatitis to cirrhosis [8], hepatitis B virus may cause genetic recombination and the activation of oncogenes such as ‘forkhead box protein M1’ (FOXM1) [9]. Hepatitis B virus may cause tumor suppressor gene inactivation after its viral DNA integrates into the host genome [10,11,12]

Methods

Results

Conclusion