Hypoxia‐inducible factor‐1α/interleukin‐1β signaling enhances hepatoma epithelial–mesenchymal transition through macrophages in a hypoxic‐inflammatory microenvironment

The development and progression of hepatocellular carcinoma (HCC) is dependent on its local microenvironment. Hypoxia and inflammation are two critical factors that shape the HCC microenvironment; however, the interplay between the two factors and the involvement of cancer cells under such conditions remain poorly understood. We found that tumor-associated macrophages (TAMs), the primary pro-inflammatory cells within tumors, secreted more interleukin (IL)-1β under moderate hypoxic conditions due to increased stability of hypoxia inducible factor (HIF)-1α. Under persistent and severe hypoxia, we found that the necrotic debris of HCC cells induced potent IL-1β release by TAMs with an M2 phenotype. We further confirmed that the necrotic debris-induced IL-1β secretion was mediated via the TLR4/TRIF/NF-κB signaling in a similar but not identical fashion as lipopolysaccharide-induced inflammation. Using mass spectrometry, we identified a group of proteins with O-linked glycosylation to be responsible for the necrotic debris-induced IL-1β secretion. Following the increase of IL-1β in the local microenvironment, the synthesis of HIF-1α was up-regulated by IL-1β in HCC cells via cyclooxygenase-2. The epithelial-mesenchymal transition (EMT) of HCC cells was enhanced by overexpression of HIF-1α. We further showed that IL-1β promoted HCC metastasis in mouse models and was predictive of poor prognosis in HCC patients. Conclusion: Our findings revealed a HIF-1α/IL-1β signaling loop between cancer cells and TAMs in a hypoxic microenvironment, resulting in cancer cell EMT and metastasis. More importantly, our results suggest a potential role of anti-inflammatory strategy in HCC treatment. This article is protected by copyright. All rights reserved.