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LincRNA-p21 knockdown reversed tumor-associated macrophages function by promoting MDM2 to antagonize* p53 activation and alleviate breast cancer development

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Tumor-associated macrophages (TAMs) are important regulators of the complex interplay between immune system and breast cancer. TAMs fuel the cancer progression and metastasis by reprogramming their specific functional phenotype in cancer settings. Therefore, it is important to clarify the mechanisms of shaping specific functional phenotype of macrophages in tumor milieu. LncRNA profiles of TAMs were identified by LncRNA microarray. Flow cytometry was used to detect the surface markers of TAMs. The co-localization among lincRNA-p21, p53 and Mouse Double Minute 2 (MDM2) was identified by FISH probe and immunofluorescence. PyVT-MMTV and BALB/c mice were used for in vivo analysis. In the present work, we found that lincRNA-p21 significantly up-regulated in 4T1 educated macrophages. LincRNA-p21 knockdown facilitated macrophage polarization into pro-inflammatory M1 in tumor microenvironment, which might be caused by MDM2 eliciting proteasome-dependent degradation to p53 and activated NF-κB and STAT3 pathway. TAMs with lincRNA-p21 knockdown induced cancer cell apoptosis, inhibited tumor cell migration and invasion. In vivo, lincRNA-p21 knockdown macrophage adoptive transfer could alleviate breast cancer progression. Our results indicated that lincRNA-p21 was a key regulator of TAMs function in tumor milieu. Our data also shed a light on novel therapeutic targets of tumors characterized by monocytes/macrophages infiltration.

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Abbreviations

ACK:

Red blood cell lysis buffer

CCK-8:

Cell counting kit-8

CTL:

Cytotoxic T lymphocyte

GO:

Gene ontology

LLC:

Lewis lung carcinoma

lncRNA:

Long non-coding RNA

miRNA:

Small RNA

NK:

Natural killer

ROS:

Reactive oxygen species

siRNA:

Small interfering RNA

SPF:

Specific pathogen-free

TAMs:

Tumor-associated macrophages

4T1CM:

4T1 mouse breast tumor cell supernatant

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Acknowledgements

This work was supported by Key University Science Research Project of Jiangsu Province (Grant No. 16KJA320005), the Social Development Foundation of Jiangsu Province (Grant No. BE2016716). The maternal and child project in Jiangsu Province (Grant No. F201511); Changzhou applied basic research project (CJ20180037).

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Author notes

  1. Lining Zhou, Yu Tian and Fang Guo contributed equally to this work.

Authors and Affiliations

  1. International Genome Center, Jiangsu University, 301 Xuefu Road, Zhenjiang, 212013, Jiangsu, China

    Lining Zhou, Yu Tian, Jiali Li, Huaxi Xu & Zhaoliang Su

  2. Department of Immunology, Jiangsu University, Zhenjiang, 212013, China

    Lining Zhou, Yu Tian, Jiali Li, Huaxi Xu & Zhaoliang Su

  3. The Central Laboratory, Changzhou Woman and Children Health Hospital Affiliated to Nanjing Medical University, Changzhou, 213003, Jiangsu, China

    Fang Guo & Bin Yu

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  1. Lining Zhou
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Contributions

LZ, YT and FG did most experiment, prepared Figs. 1, 2, 3 and 4, BY and JL prepared Figs. 5 and 6, ZS and HX designed the project, ZS prepared the manuscript.

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Correspondence to Zhaoliang Su.

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Zhou, L., Tian, Y., Guo, F. et al. LincRNA-p21 knockdown reversed tumor-associated macrophages function by promoting MDM2 to antagonize* p53 activation and alleviate breast cancer development. Cancer Immunol Immunother 69, 835–846 (2020). https://doi.org/10.1007/s00262-020-02511-0

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