Title:Sildenafil Inhibits the Growth and Epithelial-to-mesenchymal Transition
of Cervical Cancer via the TGF-β1/Smad2/3 Pathway
Volume: 23
Issue: 2
关键词:
西地那非，宫颈癌，上皮细胞向间质转化，侵袭，迁移，铂。
摘要:
Aims: The study aims to explore new potential treatments for cervical cancer.
Background: Cervical cancer is the second most common cancer in women, causing >250,000 deaths
worldwide. Patients with cervical cancer are mainly treated with platinum compounds, which often
cause severe toxic reactions. Furthermore, the long-term use of platinum compounds can reduce the
sensitivity of cancer cells to chemotherapy and increase the drug resistance of cervical cancer. Therefore,
exploring new treatment options is meaningful for cervical cancer.
Objective: The present study was to investigate the effect of sildenafil on the growth and epithelial-tomesenchymal
transition (EMT) of cervical cancer.
Methods: HeLa and SiHa cells were treated with sildenafil for different durations. Cell viability,
clonogenicity, wound healing, and Transwell assays were performed. The levels of transforming
growth factor-β1 (TGF-β1), transforming growth factor-β type I receptor (TβRI), phosphorylated (p-)
Smad2 and p-Smad3 in cervical cancer samples were measured. TGF-β1, Smad2 or Smad3 were overexpressed
in HeLa cells, and we measured the expression of EMT marker proteins and the changes in
cell viability, colony formation, etc. Finally, HeLa cells were used to establish a nude mouse xenograft
model with sildenafil treatment. The survival rate of mice and the tumor size were recorded.
Results: High concentrations of sildenafil (1.0-2.0 μM) reduced cell viability, the number of HeLa and
SiHa colonies, and the invasion/migration ability of HeLa and SiHa cells in a dose- and time-dependent
manner. The expression of TGF-β1, TβRI, p-Smad2 and p-Smad3 was significantly enhanced in cervical
cancer samples and cervical cancer cell lines. Sildenafil inhibited the expression of TGF-β1-induced
EMT marker proteins (Snail, vimentin, Twist, E-cadherin and N-cadherin) and p-Smad2/3 in HeLa
cells. Overexpression of TGF-β1, Smad2, and Smad3 reversed the effect of sildenafil on EMT, viability,
colony formation, migration, and invasion ability of HeLa cells. In the in vivo study, sildenafil significantly
increased mouse survival rates and suppressed xenograft growth.
Conclusion: Sildenafil inhibits the proliferation, invasion ability, and EMT of human cervical cancer
cells by regulating the TGF-β1/Smad2/3 pathway.
