LincRNA-p21 Knockdown Reversed Tumor-associated Macrophages Function by Promoting MDM2 to Antagonize* P53 Activation and Alleviate Breast Cancer Development

Overview

Journal Cancer Immunol Immunother

Specialties Allergy & Immunology
Oncology
Pharmacology

Date 2020 Feb 17

PMID 32062693

Citations 32

Authors

Lining Zhou

Yu Tian

Fang Guo

Bin Yu

Jiali Li

Huaxi Xu

Zhaoliang Su

Affiliations

Soon will be listed here.

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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References

Castellano J, Navarro A, Vinolas N, Marrades R, Moises J, Cordeiro A . LincRNA-p21 Impacts Prognosis in Resected Non-Small Cell Lung Cancer Patients through Angiogenesis Regulation. J Thorac Oncol. 2016; 11(12):2173-2182. DOI: 10.1016/j.jtho.2016.07.015. View

Matsumoto A, Jinno H, Ando T, Fujii T, Nakamura T, Saito J . Biological markers of invasive breast cancer. Jpn J Clin Oncol. 2015; 46(2):99-105. DOI: 10.1093/jjco/hyv153. View

Mantovani A, Marchesi F, Malesci A, Laghi L, Allavena P . Tumour-associated macrophages as treatment targets in oncology. Nat Rev Clin Oncol. 2017; 14(7):399-416. PMC: 5480600. DOI: 10.1038/nrclinonc.2016.217. View

Murray P . Macrophage Polarization. Annu Rev Physiol. 2016; 79:541-566. DOI: 10.1146/annurev-physiol-022516-034339. View

Tang S, Zheng B, Xiong X . LincRNA-p21: Implications in Human Diseases. Int J Mol Sci. 2015; 16(8):18732-40. PMC: 4581268. DOI: 10.3390/ijms160818732. View

Qiu S, Waaijer S, Zwager M, de Vries E, van der Vegt B, Schroder C . Tumor-associated macrophages in breast cancer: Innocent bystander or important player?. Cancer Treat Rev. 2018; 70:178-189. DOI: 10.1016/j.ctrv.2018.08.010. View

Jin X, Yao T, Zhou Z, Zhu J, Zhang S, Hu W . Advanced Glycation End Products Enhance Macrophages Polarization into M1 Phenotype through Activating RAGE/NF-κB Pathway. Biomed Res Int. 2015; 2015:732450. PMC: 4465680. DOI: 10.1155/2015/732450. View

Inoue K, Fry E, Frazier D . Transcription factors that interact with p53 and Mdm2. Int J Cancer. 2015; 138(7):1577-85. PMC: 4698088. DOI: 10.1002/ijc.29663. View

Ngambenjawong C, Gustafson H, Pun S . Progress in tumor-associated macrophage (TAM)-targeted therapeutics. Adv Drug Deliv Rev. 2017; 114:206-221. PMC: 5581987. DOI: 10.1016/j.addr.2017.04.010. View

10.

Biswas S, Mantovani A . Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nat Immunol. 2010; 11(10):889-96. DOI: 10.1038/ni.1937. View

11.

Schmitt A, Chang H . Long Noncoding RNAs in Cancer Pathways. Cancer Cell. 2016; 29(4):452-463. PMC: 4831138. DOI: 10.1016/j.ccell.2016.03.010. View

12.

Bussard K, Mutkus L, Stumpf K, Gomez-Manzano C, Marini F . Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Res. 2016; 18(1):84. PMC: 4982339. DOI: 10.1186/s13058-016-0740-2. View

13.

Ferre F, Colantoni A, Helmer-Citterich M . Revealing protein-lncRNA interaction. Brief Bioinform. 2015; 17(1):106-16. PMC: 4719072. DOI: 10.1093/bib/bbv031. View

14.

Tan H, Wang N, Li S, Hong M, Wang X, Feng Y . The Reactive Oxygen Species in Macrophage Polarization: Reflecting Its Dual Role in Progression and Treatment of Human Diseases. Oxid Med Cell Longev. 2016; 2016:2795090. PMC: 4837277. DOI: 10.1155/2016/2795090. View

15.

Fan Y, Mao R, Yang J . NF-κB and STAT3 signaling pathways collaboratively link inflammation to cancer. Protein Cell. 2013; 4(3):176-85. PMC: 4875500. DOI: 10.1007/s13238-013-2084-3. View

16.

Soysal S, Tzankov A, Muenst S . Role of the Tumor Microenvironment in Breast Cancer. Pathobiology. 2015; 82(3-4):142-52. DOI: 10.1159/000430499. View

17.

Aras S, Zaidi M . TAMeless traitors: macrophages in cancer progression and metastasis. Br J Cancer. 2017; 117(11):1583-1591. PMC: 5729447. DOI: 10.1038/bjc.2017.356. View

18.

Li L, Ng D, Mah W, Almeida F, Rahmat S, Rao V . A unique role for p53 in the regulation of M2 macrophage polarization. Cell Death Differ. 2014; 22(7):1081-93. PMC: 4572866. DOI: 10.1038/cdd.2014.212. View

19.

Sica A, Erreni M, Allavena P, Porta C . Macrophage polarization in pathology. Cell Mol Life Sci. 2015; 72(21):4111-26. PMC: 11113543. DOI: 10.1007/s00018-015-1995-y. View

20.

King T, Morrow M . Surgical issues in patients with breast cancer receiving neoadjuvant chemotherapy. Nat Rev Clin Oncol. 2015; 12(6):335-43. DOI: 10.1038/nrclinonc.2015.63. View