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GRP78 facilitates M2 macrophage polarization and tumour progression

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Abstract

This study investigated the regulation of GRP78 in tumour-associated macrophage polarization in lung cancer. First, our results showed that GRP78 was upregulated in macrophages during M2 polarization and in a conditioned medium derived from lung cancer cells. Next, we found that knocking down GRP78 in macrophages promoted M1 differentiation and suppressed M2 polarization via the Janus kinase/signal transducer and activator of transcription signalling. Moreover, conditioned medium from GRP78- or insulin-like growth factor 1-knockdown macrophages attenuated the survival, proliferation, and migration of lung cancer cells, while conditioned medium from GRP78-overexpressing macrophages had the opposite effects. Additionally, GRP78 knockdown reduced both the secretion of insulin-like growth factor 1 and the phosphorylation of the insulin-like growth factor 1 receptor. Interestingly, insulin-like growth factor 1 neutralization downregulated GRP78 and suppressed GRP78 overexpression-induced M2 polarization. Mechanistically, insulin-like growth factor 1 treatment induced the translocation of GRP78 to the plasma membrane and promoted its association with the insulin-like growth factor 1 receptor. Finally, IGF-1 blockade and knockdown as well as GRP78 knockdown in macrophages inhibited M2 macrophage-induced survival, proliferation, and migration of lung cancer cells both in vitro and in vivo.

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All data generated or analyzed during this study are included in this published article.

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Funding

This work was supported by the National Natural Science Foundation of China (81802290) and National Multidisciplinary Cooperative Diagnosis and Treatment Capacity Building Project for Major Diseases (Lung Cancer, grant number: z027002).

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Authors and Affiliations

  1. Department of General Thoracic Surgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, China

    Heng Zhang, Lin Hang, Chun-Fang Zhang, Chao-Jun Duan & Yuan-Da Cheng

  2. Xiangya Lung Cancer Center, Xiangya Hospital, Central South University, Changsha, 410008, Hunan Province, China

    Heng Zhang, Chun-Fang Zhang & Yuan-Da Cheng

  3. Hunan Engineering Research Center for Pulmonary Nodules Precise Diagnosis and Treatment, Changsha, 410008, Hunan Province, China

    Heng Zhang, Chun-Fang Zhang, Chao-Jun Duan & Yuan-Da Cheng

  4. Department of Thoracic Surgery, Affiliated Hospital of Jining Medical University, Jining Medical University, Jining, 272029, Shandong Province, China

    Shao-Qiang Wang

  5. Department of Thoracic Surgery, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan Province, China

    Li Wang

  6. Hunan Key Laboratory of Early Diagnosis and Precise Treatment of Lung Cancer, The Second Xiangya Hospital of Central South University, Changsha, 410011, Hunan Province, China

    Li Wang

  7. Department of Cardiothoracic Surgery, Xiangya Hospital, Central South University, No. 87, Xiangya Road, Changsha, 410008, Hunan Province, China

    Dong-Kai Wu & Ri Chen

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  1. Heng Zhang
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  2. Shao-Qiang Wang
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  3. Lin Hang
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  4. Chun-Fang Zhang
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  5. Li Wang
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  8. Dong-Kai Wu
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  9. Ri Chen
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Correspondence to Ri Chen.

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The study was designed in accordance with the Declaration of Helsinki and approved by the ethics committee of Central South University in China.

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Zhang, H., Wang, SQ., Hang, L. et al. GRP78 facilitates M2 macrophage polarization and tumour progression. Cell. Mol. Life Sci. 78, 7709–7732 (2021). https://doi.org/10.1007/s00018-021-03997-2

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