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 1β (IL‐1β) under moderate hypoxic conditions due to increased stability of hypoxia inducible factor 1α (HIF‐1α). Under persistent and severe hypoxia, we found that the necrotic debris of HCC cells induced potent IL‐1β release by tumor‐associated macrophages with an M2 phenotype. We further confirmed that the necrotic debris–induced IL‐1β secretion was mediated through Toll‐like receptor 4/TIR domain–containing adapter‐inducing interferon‐β/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‐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 through cyclooxygenase‐2. The epithelial–mesenchymal transition 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 an HIF‐1α/IL‐1β 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)

中文翻译：

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HIF-1α/IL-1β 信号在缺氧炎症微环境中通过巨噬细胞增强肝癌上皮间质转化

肝细胞癌 (HCC) 的发生和进展取决于其局部微环境。缺氧和炎症是塑造 HCC 微环境的两个关键因素；然而，这两个因素之间的相互作用以及在这种情况下癌细胞的参与仍然知之甚少。我们发现，由于缺氧诱导因子 1α（HIF-1α）的稳定性增加，肿瘤相关巨噬细胞（肿瘤内的主要促炎细胞）在中度缺氧条件下分泌更多的白细胞介素 1β（IL-1β）。在持续和严重缺氧的情况下，我们发现 HCC 细胞的坏死碎片诱导具有 M2 表型的肿瘤相关巨噬细胞有效释放 IL-1β。我们进一步证实，坏死碎片诱导的 IL-1β 分泌是通过含有 Toll 样受体 4/TIR 结构域的接头诱导干扰素-β/核因子κ-轻链增强子在类似的激活 B 细胞信号传导中介导的。脂多糖诱导的炎症，但不完全相同。使用质谱法，我们鉴定了一组具有 O-连接糖基化的蛋白质，这些蛋白质负责坏死碎片诱导的 IL-1β 分泌。随着局部微环境中IL-1β的增加，HCC细胞中IL-1β通过环氧合酶2上调HIF-1α的合成。HIF-1α 的过表达增强了 HCC 细胞的上皮间质转化。我们进一步表明，IL-1β 促进小鼠模型中的 HCC 转移，并预示着 HCC 患者的预后不良。结论：我们的研究结果揭示了在缺氧微环境中癌细胞和肿瘤相关巨噬细胞之间的 HIF-1α/IL-1β 信号回路，导致癌细胞上皮间质转化和转移；更重要的是，我们的结果表明抗炎策略在 HCC 治疗中的潜在作用。（肝病学 2018；67：1872-1889）