Figure 2.

The diverse range of signals in the TME which could induce HMOX1 expression. HMOX1 mRNA expression is induced by a range of molecular and physical signals. The figure highlights common physical characteristics (hypoxia), metabolic by-products (ROS) and cytokines commonly associated with the TME which could induce the expression of HO-1 in cancer. In normal conditions, the transcription factor Nrf2 is inhibited by Keap1 which prevents nuclear translocation and promotes its proteasomal degradation. ROS generated by oxidative stress inhibit the interaction between Keap1 and Nrf2, allowing Nrf2 to translocate to the nucleus and bind to the ARE of the HMOX1 gene. In the presence of heme, Bach1 is prevented from inhibiting Nrf2 access to the ARE allowing the expression of HMOX1. Under conditions of hypoxia, the transcription factor HIF-1α escapes proteasomal degradation and translocates into the nucleus where it forms a complex with HIF-1β and binds to HRE to up-regulate HMOX1 gene expression. Cytokines such as IL-10 and IL-6 can induce expression via the JAK/STAT3 pathway, while IL-1α and TNF-α induced HMOX1 expression through a PKC, Ca²⁺ signaling, and PLA2 dependent pathway and AP-1 element in the promoter region.