The Promoting Effect and Mechanism of Nrf2 on Cell Metastasis in Cervical Cancer

Abstract Background Epithelial-mesenchymal transition (EMT) and anoikis are initial and pivotal steps during the metastatic process. Although higher levels of Nrf2 are associated with aggressive tumor behaviors such as proliferation, invasion and migration in cervical cancer, the detailed mechanism of Nrf2 in cervical cancer metastasis, especially EMT and anoikis, remains unclear.Methods We investigated the expression of Nrf2 in patients with or without cervical cancer lymph node metastasis through immunohistochemistry (IHC). Wound healing assay and transwell analysis were used to evaluate the migration ability of different cervical cancer cells including Nrf2 knockout and Nrf2 overexpression cells. Western blot was used to verify the expression level of Nrf2, the EMT associated markers and anoikis associated proteins in different situations. Flow cytometry assays were used to detect the apoptosis of cervical cancer cells. A xenograft assay was used to verify the metastatic function of Nrf2 in vivo.Results Nrf2 was highly expressed in patients with cervical cancer lymph node metastasis. And Nrf2 was proved to enhance the migration ability of HeLa and SiHa cells. In addition, Nrf2 was positively correlated with EMT processes and negatively associated with anoikis in cervical cancer through Snail1-dependent pathway. In vivo, a xenograft assay also showed that Nrf2 facilitated both pulmonary and lymphatic distant metastasis of cervical cancer.Conclusion Nrf2 could play a crucial role in the metastasis of cervical cancer by enhancing EMT and resistance to anoikis by promoting the expression of Snail1.