Abstract
Simple SummaryThe high recurrence risk and poor prognosis of metastatic endometrial cancer are the main focus of interventional therapy. In view of this, we established in vitro and in vivo metastasis models and explored the underlying mechanisms of the epithelial-mesenchymal transition (EMT) process, cell migration ability, and metastasis in response to isoliquiritigenin (ISL). The presented in vitro and in vivo preclinical studies both demonstrated that ISL efficiently suppressed endometrial cancer cell migration and reduced the HEC-1A-LUC tumor metastasis in nude mice through inhibiting TGF-β/Smad signaling pathway. These findings shed the light for further research to highlight the ISL potential in endometrial cancer metastasis.Endometrial cancer is a common gynecological cancer with a poor prognosis, mostly attributed to tumor metastasis. Epithelial–mesenchymal transition (EMT) can be mediated via transforming growth factor beta (TGF-β) signaling pathway, facilitating the ability of cancer cell invasion and migration. Isoliquiritigenin (ISL) is a flavonoid derived from licorice with reported antineoplastic activities. This study aims to investigate the anti-metastatic potential of ISL on endometrial cancer both in vitro and in vivo. First, human endometrial cancer cell lines (HEC-1A, Ishikawa, and RL95-2) were treated with ISL and then subjected to functional assays such as migration assay as well as molecular analyses including immunoblotting, immunofluorescence and RT-qPCR. In addition, HEC-1A-LUC cells were implanted into female nude mice and treated with ISL by intraperitoneal injection for four weeks. Results showed that ISL inhibited cell migration and reversed the effect of TGF-β on the expression of E-cadherin, N-cadherin, vimentin, α-SMA, p-Smad3, and TWIST1/2 In vitro. Interestingly, In vivo study revealed that ISL reduced peritoneal dissemination and serum level of TGF-β1, as well as decreased the expression levels of N-cadherin, p-Smad2/3, TWIST1/2, while increased E-cadherin. Overall, ISL reverses the EMT through targeting the TGF-β/Smad signaling pathway and features a potential therapeutic treatment for metastatic endometrial cancer.
Highlights
Endometrial cancer is the most common gynecological malignancy in women from Western countries which usually occurs later in life at menopause [1]
The results showed that treatment with ISL at concentrations 10 μM and 20 μM significantly reduced the survival rate of HEC-1A, Ishikawa, and RL95-2 cell lines compared with untreated control group (p < 0.01, Figure 1a–c)
The results showed that treatment of HEC-1A and Ishikawa cells with TGF-β1 for 4 h and 8 h significantly increased the phosphorylation of Smad3 (p-Smad3) protein expression (p < 0.05), ISL co-treatment significantly decreased p-Smad3 protein expression in HEC-1A (Figure 6a,b) and Ishikawa cells (Figure 6c,d) at 8 h (p < 0.05)
Summary
Endometrial cancer is the most common gynecological malignancy in women from Western countries which usually occurs later in life at menopause [1]. Early diagnosis of endometrial cancer as well as slowing tumor metastasis are essential approaches for better patients’ prognosis. Epithelial-mesenchymal transition (EMT) plays an important mechanism in mediating metastasis. EMT is a process that allows epithelial cells to transition into mesenchymal cells, promoting tumor progression [6]. A previous study has shown that the status of EMT affects the prognosis of patients with endometrial cancer [7]. Loss of E-cadherin expression in the epithelial cells results in losing cell adhesion and cellular polarity, considered a hallmark of EMT process. Decreased E-cadherin expression is coupled with increased mesenchymal N-cadherin expression level which in turn enhance cells ability to migrate and invade as shown in several studies [8,9,10]. Other mesenchymal markers in EMT include vimentin, fibronectin and α-smooth muscle actin (α-SMA), which are markers for myofibroblast [11]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
