The paradoxical role of Nrf2 in tumor biology.

Nrf2 is used as a cell protector by mediating many downstream genes which express phase II detoxifying and antioxidant enzymes. Recently, large numbers of experiments have shown Nrf2 and its downstream genes are found to be overexpressed in many human tumors. Numerous evidences unveil that Nrf2 protects the normal cells while promoting the malignant tumor's progression. The paradoxical role of Nrf2 has not been clearly elucidated before. Here, we review the suppressor or oncogene roles of Nrf2 in different stages of specific tumors with respect to the newest studies. Further, we suspect that the hypoxic microenvironment around the tumors is the main crux which determines the role of Nrf2 in the tumor initiation, invasion, and metastasis. In the initiation of tumors, Nrf2 or Keap1 genes get mutations under the oxidative stress; as a result, the tumor cells obtain the advantage to growth. At the later stages, the hypoxic microenvironment around the malignant tumors has a profound influence on the character of Nrf2. Under the hypoxic microenvironment, expression of certain downstream genes of Nrf2 involved in angiogenesis are obviously elevated; other transcription factors derived from hypoxic microenvironment interact with Nrf2 and in that way promote or inhibit the invasion and metastasis.