Hypoxia-inducible factor-1/interleukin-1 signaling enhances hepatoma epithelial-mesenchymal transition through macrophages in a hypoxic-inflammatory microenvironment

The development and progression of hepatocellular carcinoma (HCC) are 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, the primary proinflammatory cells within tumors, secreted more interleukin 1 (IL-1) under moderate hypoxic conditions due to increased stability of hypoxia inducible factor 1 (HIF-1). Under persistent and severe hypoxia, we found that the necrotic debris of HCC cells induced potent IL-1 release by tumor-associated macrophages with an M2 phenotype. We further confirmed that the necrotic debris-induced IL-1 secretion was mediated through Toll-like receptor 4/TIR domain-containing adapter-inducing interferon-/nuclear factor kappa-light-chain-enhancer of activated B cells signaling in a similar, but not identical, fashion to 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-1 secretion. Following the increase of IL-1 in the local microenvironment, the synthesis of HIF-1 was up-regulated by IL-1 in HCC cells through cyclooxygenase-2. The epithelial-mesenchymal transition of HCC cells was enhanced by overexpression of HIF-1. We further showed that IL-1 promoted HCC metastasis in mouse models and was predictive of poor prognosis in HCC patients. Conclusion: Our findings revealed an HIF-1/IL-1 signaling loop between cancer cells and tumor-associated macrophages in a hypoxic microenvironment, resulting in cancer cell epithelial-mesenchymal transition and metastasis; more importantly, our results suggest a potential role of an anti-inflammatory strategy in HCC treatment. (Hepatology 2018;67:1872-1889)