TLR4 Agonist and Hypoxia Synergistically Promote the Formation of TLR4/NF-kappa B/HIF-1 alpha Loop in Human Epithelial Ovarian Cancer

Inflammation and hypoxia are involved in numerous cancer progressions. Reportedly, the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-kappa B) pathway and hypoxia-inducible factor-1 alpha (HIF-1 alpha) are activated and closely related to the chemoresistance and poor prognosis of epithelial ovarian cancer (EOC). However, the potential correlation between TLR4/NF-kappa B and HIF-1 alpha remains largely unknown in EOC. In our study, the possible positive correlation among TLR4, NF-kappa B, and HIF-1 alpha proteins was investigated in the EOC tissues. Our in vitro results demonstrated that LPS can induce and activate HIF-1 alpha through the TLR4/NF-kappa B signaling in A2780 and SKOV3 cells. Moreover, hypoxia-induced TLR4 expression and the downstream transcriptional activity of NF-kappa B were HIF-1 alpha-dependent. The cross talk between the TLR4/NF-kappa B signaling pathway and HIF-1 alpha was also confirmed in the nude mice xenograft model. Therefore, we first proposed the formation of a TLR4/NF-kappa B/HIF-1 alpha loop in EOC. The positive feedback loop enhanced the susceptibility and responsiveness to inflammation and hypoxia, which synergistically promote the initiation and progression of EOC. The novel mechanism may act as a future therapeutic candidate for the treatment of EOC.