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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
Notch1 Affects Chemo-resistance Through Regulating Epithelial-Mesenchymal Transition (EMT) in Epithelial Ovarian
Xue-Qian Qian1, Sang-Sang Tang1, Yuan-Ming Shen1
1Women's Reproductive Health Key Laboratory of Zhejiang Province; Department of Gynecologic Oncology, Women's Hospital, School of Medicine, Zhejiang University, and Hangzhou, China.
Abstract:
Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, chemo-resistance is the main cause for treatment failure. Our previous studies have found that SKOV3 could promote immune escape and tumor progression via Notch1 pathway. Therefore, Notch1 is suspected to be involved in chemo-resistance. The current study is to investigate the possible mechanisms of platinum-resistance in epithelial ovarian cancer mediated by Notch1. Methods: The expressions of Notch1, Snail, MMP-2, N-cadherin, Vimentin and E-cadherin were detected by Western-blot. A stable high expression or low expression of Notch1 in ovarian cancer cells was established by using lentiviral gene engineering. The cell migration and invasion ability were observed by scratch test and transwell test. Cell apoptosis rate and cell cycle were analyzed by flow cytometry. Results: The expression levels of Notch1, Snail, MMP-2, N-cadherin and Vimentin in ovarian cancer were high, while the expression levels of E-cadherin were low.Notch1 promoted the expression of Snail, vimentin, N-cadherin and MMP2 protein, but inhibiting the expression of E-cadherin, promoting cell migration and invasion. Notch1 affected apoptosis of cells through Epithelial-Mesenchymal Transition (EMT), increasing the proportion of cells in S phase and G2 phase, thus affecting drug resistance. Conclusion: Notch1 affects EOC cells chemo-resistance by regulating EMT. This may provide a new target for the treatment of ovarian cancer.
Insights
Notch1 signaling promotes platinum resistance in epithelial ovarian cancer (EOC) by driving Epithelial-Mesenchymal Transition (EMT). Targeting Notch1 may offer a new therapeutic strategy for overcoming chemo-resistance in EOC patients.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Epithelial ovarian cancer (EOC) is a leading cause of gynecological cancer mortality.
- Chemo-resistance significantly contributes to treatment failure in EOC.
- Previous research linked Notch1 pathway to immune escape and tumor progression in EOC.
Purpose of the Study:
- To investigate the role of Notch1 in platinum-resistance mechanisms in epithelial ovarian cancer.
- To elucidate how Notch1 signaling influences chemo-resistance in EOC cells.
- To explore Notch1 as a potential therapeutic target for overcoming EOC chemo-resistance.
Main Methods:
- Western blot analysis to assess protein expression (Notch1, Snail, MMP-2, N-cadherin, Vimentin, E-cadherin).
- Lentiviral gene engineering to establish stable high/low Notch1 expression in ovarian cancer cells.
- Cell migration/invasion assays (scratch and Transwell tests) and flow cytometry (apoptosis, cell cycle analysis).
Main Results:
- Elevated Notch1, Snail, MMP-2, N-cadherin, and Vimentin expression, with decreased E-cadherin, observed in ovarian cancer.
- Notch1 overexpression promoted Snail, vimentin, N-cadherin, and MMP2, while inhibiting E-cadherin, enhancing cell migration and invasion.
- Notch1 influenced cell apoptosis and cell cycle progression (S and G2 phases) via Epithelial-Mesenchymal Transition (EMT), impacting drug resistance.
Conclusions:
- Notch1 plays a critical role in mediating chemo-resistance in epithelial ovarian cancer by regulating EMT.
- Targeting the Notch1 pathway presents a promising new therapeutic strategy for EOC treatment.
- Understanding Notch1's role in EMT is key to developing effective therapies against platinum-resistant EOC.
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