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HIF-1α/IL-8 axis in hypoxic macrophages promotes esophageal cancer progression by enhancing PD-L1 expression

Cancer Gene Therapy volume 30, pages 358–367 (2023)Cite this article

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Abstract

Esophageal cancer (EC) is a malignancy with poor prognosis and high mortality. Hypoxic microenvironment has also been proved to be an important feature of tumors. Herein, we mainly studied the influence of hypoxia-treated tumor-associated macrophages (TAMs) on EC malignant phenotype and related molecular mechanism. In this paper, we found that hypoxic macrophages contributed to EC cell proliferation, cell cycle progression, and metastasis. Besides, the hypoxia treatment expedited the transformation of macrophages into M2 polarization. The level of interleukin (IL)-8 was boosted in macrophages after hypoxia treatment. Moreover, hypoxia treatment heightened IL-8 secretion by macrophages via positively regulating hypoxia-inducible factor-1α (HIF-1α) expression. The IL-8 secreted by hypoxic macrophages facilitated EC cell proliferation, cell cycle progression, and metastasis by elevating ligand of programmed death 1 (PD-L1) expression. In the end, IL-8 also expedited EC tumorigenesis in vivo. In conclusion, HIF-1α/IL-8 axis in hypoxic macrophages could expedite EC advancement by upregulating PD-L1 level, which might deliver a novel thought for EC cure.

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Fig. 1: Hypoxic macrophages stimulated EC cell development.
Fig. 2: Hypoxic macrophages stimulated EC cell metastasis.
Fig. 3: Hypoxia treatment polarized macrophages toward a M2 phenotype.
Fig. 4: Hypoxia treatment heightened IL-8 secretion by macrophages via upregulating HIF-1α expression.
Fig. 5: IL-8 from hypoxic macrophages stimulated EC cell development by upregulating PD-L1 expression.
Fig. 6: IL-8 from hypoxic macrophages stimulated EC cell metastasis by upregulating PD-L1 expression.
Fig. 7: Knockdown of IL-8 inhibited the EC tumorigenesis in vivo.

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Data archiving will be made available on reasonable request, all of the authors are responsible to the data.

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Author notes

  1. These authors contributed equally: Shuai Song, Yahui Zhang.

Authors and Affiliations

  1. Department of Thoracic Surgery, Beijing Friendship Hospital, Capital Medical University, Beijing, China

    Shuai Song, Xinchun Duan, Chunquan Liu, Yanlin Du, Xiaoran Wang, Yi Luo & Yong Cui

  2. Department of Pharmacy, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China

    Yahui Zhang

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Contributions

SS and YC designed the study. SS YZ and XD carried out the experiments. CL and YD assisted with the experiments. XW and YL conducted data analysis and interpretation. SS wrote the manuscript. YC supervised the project. All authors have read and approved the published version of the manuscript.

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Correspondence to Yong Cui.

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Song, S., Zhang, Y., Duan, X. et al. HIF-1α/IL-8 axis in hypoxic macrophages promotes esophageal cancer progression by enhancing PD-L1 expression. Cancer Gene Ther 30, 358–367 (2023). https://doi.org/10.1038/s41417-022-00551-5

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