Hypoxia‐inducible factor‐1α/interleukin‐1β signaling enhances hepatoma epithelial–mesenchymal transition through macrophages in a hypoxic‐inflammatory microenvironment
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- Jingying Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Qi Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Yu Lou
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Qihan Fu
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Qi Chen
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Tao Wei
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Jiaqi Yang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Jinlong Tang
- Department of Pathology, the Second Affiliated Hospital,Zhejiang University School of Medicine,Hangzhou,China
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- Jianxin Wang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Yiwen Chen
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Xiaoyu Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Jian Zhang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Xueli Bai
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
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- Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery, the Second Affiliated Hospital,Zhejiang University School of Medicine
Description
<jats:p>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 <jats:italic toggle="yes">O</jats:italic>‐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. <jats:italic toggle="yes">Conclusion</jats:italic>: 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. (H<jats:sc>epatology</jats:sc> 2018;67:1872‐1889)</jats:p>
Journal
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- Hepatology
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Hepatology 67 (5), 1872-1889, 2018-03-26
Ovid Technologies (Wolters Kluwer Health)
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Details 詳細情報について
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- CRID
- 1362544419372830592
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- ISSN
- 15273350
- 02709139
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- Data Source
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- Crossref