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MIF as a master regulator in macrophage-induced chemotherapy resistance in esophageal squamous cell carcinoma
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  • Yi Lin Ren,
  • Yi Chen Zang,
  • Li Wen Qi,
  • Xue Li Wang,
  • * Yu Fang Xie a,
  • Fan Ping Li,
  • Ya Li,
  • Le Le Xue,
  • Kai Ge Yang,
  • Wei Nan Wang,
  • Meng Meng Zhao,
  • Jia Liu,
  • Cheng Hua Luo,
  • Wei Hua Liang,
  • Hai Jun Zhang,
  • Xi Hua Shen,
  • Wen Hu Zhou,
  • Fei Jing,
  • Wei Gang Chen,
  • Wenyi Gu,
  • Liang Hai Wang,
  • Feng Li,
  • Jian Ming Hu
Yi Lin Ren
First Affiliated Hospital of Shihezi University School of Medicine
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Yi Chen Zang
First Affiliated Hospital of Shihezi University School of Medicine
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Li Wen Qi
First Affiliated Hospital of Shihezi University School of Medicine
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Xue Li Wang
First Affiliated Hospital of Shihezi University School of Medicine
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* Yu Fang Xie a
First Affiliated Hospital of Shihezi University School of Medicine
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Fan Ping Li
First Affiliated Hospital of Shihezi University School of Medicine
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Ya Li
First Affiliated Hospital of Shihezi University School of Medicine
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Le Le Xue
First Affiliated Hospital of Shihezi University School of Medicine
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Kai Ge Yang
First Affiliated Hospital of Shihezi University School of Medicine
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Wei Nan Wang
First Affiliated Hospital of Shihezi University School of Medicine
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Meng Meng Zhao
First Affiliated Hospital of Shihezi University School of Medicine
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Jia Liu
First Affiliated Hospital of Shihezi University School of Medicine
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Cheng Hua Luo
First Affiliated Hospital of Shihezi University School of Medicine
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Wei Hua Liang
First Affiliated Hospital of Shihezi University School of Medicine
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Hai Jun Zhang
First Affiliated Hospital of Shihezi University School of Medicine
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Xi Hua Shen
First Affiliated Hospital of Shihezi University School of Medicine
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Wen Hu Zhou
Central South University Xiangya School of Pharmaceutical Sciences
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Fei Jing
First Affiliated Hospital of Shihezi University School of Medicine
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Wei Gang Chen
First Affiliated Hospital of Shihezi University School of Medicine
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Wenyi Gu
The University of Queensland Australian Institute for Bioengineering and Nanotechnology
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Liang Hai Wang
First Affiliated Hospital of Shihezi University School of Medicine
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Feng Li
First Affiliated Hospital of Shihezi University School of Medicine
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Jian Ming Hu
First Affiliated Hospital of Shihezi University School of Medicine

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Abstract

Backgroun:Esophageal cancer is insidious, with recurrent metastasis and chemotherapy resistance as primary reasons for treatment failure. Recent interest has focused on the molecular mechanisms of tumor-associated macrophages (TAMs) in the tumor microenvironment, which remain largely unknown. Methods:TAMs were examined using both in vitro and in vivo assays. Seventy-seven normal paracancerous tissues and esophageal squamous cell carcinoma (ESCC) tumor samples were compared using immunohistochemical methods. Molecular mechanisms were identified using Transwell, Western blotting, Fluorescence-assisted cell sorting, CCK 8, and reverse transcriptase–polymerase chain reaction assays. Results: M2 TAMs were significantly elevated in ESCC tissues. M2 TAMs contributed to ESCC development and resistance to treatment both in vitro and in vivo. Elevated CD163 + TAMs in patients with ESCC correlate with an unfavorable prognosis. We found that TAMs release macrophage migration inhibitory factor (MIF), which regulates the expression of B-cell lymphoma 2 (Bcl-2), P-glycoprotein 1 (P-gp), and Bcl-2 associated X (Bax) to promote drug resistance and stimulate phosphoinositol 3-kinase (PI3K)–protein kinase B (AKT) signaling. Conclusion:Our findings demonstrate that MIF performs a functional role in the macrophage-mediated resistance of ESCC cells to cisplatin and that targeting MIF may serve as a strategy for molecular therapy.