西地那非通过 TGF-β1/Smad2/3 通路抑制宫颈癌的生长和上皮间质转化。
Sildenafil Inhibits the Growth and Epithelial-to-mesenchymal Transition of Cervical Cancer via the TGF-β1/Smad2/3 Pathway.
机构信息
Department of Obstetrics and Gynecology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, 200090, China.
Child Healthcare Department, The Affiliated Wuxi Matemity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214001, China.
出版信息
Curr Cancer Drug Targets. 2023;23(2):145-158. doi: 10.2174/1568009622666220816114543.
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.
目的
本研究旨在探索宫颈癌的新潜在治疗方法。
背景
宫颈癌是女性中第二大常见癌症，导致全球超过 25 万人死亡。宫颈癌患者主要采用铂类化合物治疗，但铂类化合物常引起严重的毒副作用。此外，长期使用铂类化合物会降低癌细胞对化疗的敏感性，并增加宫颈癌的耐药性。因此，探索新的治疗方案对宫颈癌具有重要意义。
目的
本研究旨在探讨西地那非对宫颈癌生长和上皮间质转化（EMT）的影响。
方法
用西地那非处理 HeLa 和 SiHa 细胞不同时间。进行细胞活力、集落形成、划痕愈合和 Transwell 分析。测量宫颈癌样本中转化生长因子-β1（TGF-β1）、转化生长因子-β 型 I 受体（TβRI）、磷酸化（p-）Smad2 和 p-Smad3 的水平。在 HeLa 细胞中转染 TGF-β1、Smad2 或 Smad3，测量 EMT 标志物蛋白的表达以及细胞活力、集落形成等的变化。最后，用西地那非处理 HeLa 细胞建立裸鼠异种移植模型。记录小鼠的存活率和肿瘤大小。
结果
高浓度西地那非（1.0-2.0 μM）呈剂量和时间依赖性降低 HeLa 和 SiHa 细胞活力、细胞数和侵袭/迁移能力。宫颈癌样本和宫颈癌细胞系中 TGF-β1、TβRI、p-Smad2 和 p-Smad3 的表达明显增强。西地那非抑制 TGF-β1 诱导的 EMT 标志物蛋白（Snail、波形蛋白、Twist、E-钙黏蛋白和 N-钙黏蛋白）和 HeLa 细胞中 p-Smad2/3 的表达。TGF-β1、Smad2 和 Smad3 的过表达逆转了西地那非对 HeLa 细胞 EMT、活力、集落形成、迁移和侵袭能力的影响。在体内研究中，西地那非显著提高了小鼠的存活率并抑制了异种移植的生长。
结论
西地那非通过调节 TGF-β1/Smad2/3 通路抑制人宫颈癌细胞的增殖、侵袭能力和 EMT。
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