Investigation of NRF3 gene to TNF-α dependent under hypoxia conditions in stomach cancer

Hypoxia is a condition that occurs at low oxygen levels, especially in solid tumors. ROS formation is required for the stabilization of HIF 1α, a marker of hypoxia. ROS levels that occur in the early stages of hypoxic conditions inhibit the PHD and FIH proteins responsible for the degradation of HIF 1α. In stomach cancer, immune system cells affected by a hypoxic microenvironment release TNF α. TNF α induces ROS generation both by mitochondrial pathway and NOX activation pathway. Increased ROS levels by TNF α elicit HIF 1α expressions in stomach cancer. CNC family members Nrf1, Nrf2 and Nrf3 are transcription factors that are activated under various cellular stress conditions. In contrast to Nrf1 and Nrf2, which positively regulate antioxidant gene expressions, Nrf3 expression suppresses antioxidant gene expressions. Increased gene expression of Nrf3 has led to aggressiveness in many types of cancer. In this study, Nrf3 gene expression was investigated for the first time under hypoxia conditions and dependent on TNF α in stomach cancer. Our findings showed that HIF-1α gene expression and Nrf3 gene expression were increased in AGS and MKN 45 cells in a cobalt-induced hypoxia model. Over time, HIF-1α gene expression returned to the level of the control group, while Nrf3 gene expression was significantly suppressed. While Nrf3 gene expression increased in TNF-α and cobalt treated AGS and MKN 45 cells, Nrf3 gene expression which increased with time, was suppressed at different degrees of expression in AGS and MKN 45 cells. Increased Nrf3 expression under hypoxic conditions and in the presence of TNF α may be an important gene leading to aggressiveness in stomach cancer. In addition, our results suggested for the first time that there may be a hypoxic response mechanism that suppresses Nrf3 gene expression over time under hypoxia conditions.