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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2020 | Metastasis | Research

Linc00514 promotes breast cancer metastasis and M2 polarization of tumor-associated macrophages via Jagged1-mediated notch signaling pathway

Authors: Sifeng Tao, Qiang Chen, Chen Lin, Haiying Dong

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2020

Abstract

Background

Tumor-associated macrophages (TAMs) and tumor cells are important components of the tumor microenvironment. M2 polarization of TAMs, which is a major actor in breast cancer malignancy and metastasis, can be induced by breast cancer cells. However, the potential mechanisms of the interaction between breast cancer cells and TAMs remain unclear.

Methods

The candidate breast cancer-associated long non-coding RNAs (lncRNAs) were analyzed using the GEO database. Functional assays, including MTT assay, Transwell assay, and EdU labeling detection, were performed to investigate the oncogenic role of linc00514 in breast cancer progression. The co-culture and ELISA assays were used to assess the role of linc00514 in macrophage recruitment and M2 polarization. RNA immunoprecipitation, RNA pull-down, and luciferase reporter assays were applied to determine the mechanism of linc00514 in breast cancer metastasis. Mouse xenograft models, mouse pulmonary metastatic models, and mouse primary tumor models were used to assess the role of linc00514 in M2 macrophage polarization and breast cancer tumorigenicity.

Results

Linc00514 was highly expressed in clinical breast cancer tissues and breast cancer cell lines. Overexpression of linc00514 promoted the proliferation and invasion of breast cancer cells and increased xenograft tumor volumes and pulmonary metastatic nodules. Overexpression of linc00514 also increased the percentage of macrophages expressing M2 markers CD206 and CD163. Mechanistically, linc00514 promoted Jagged1 expression in a transcriptional manner by increasing the phosphorylation of a transcription factor STAT3. Subsequently, Jagged1-mediated Notch signaling pathway promoted IL-4 and IL-6 secretions in breast cancer cells and ultimately inducing M2 polarization of macrophages.

Conclusion

Linc00514 plays an important role in regulating breast cancer tumorigenicity and M2 macrophage polarization via Jagged1-mediated Notch signaling pathway.

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Geeraerts X, Bolli E, Fendt S-M, Van Ginderachter JA. Macrophage metabolism as therapeutic target for Cancer, atherosclerosis, and obesity. Front Immunol. 2017;8:289.PubMedPubMedCentralCrossRef

Biswas SK, Allavena P, Mantovani A. Tumor-associated macrophages: functional diversity, clinical significance, and open questions. Semin Immunopathol. 2013;35(5):585–600.PubMedCrossRef

Komohara Y, Takeya M. CAFs and TAMs: maestros of the tumour microenvironment. J Pathol. 2017;241(3):313–5.PubMedCrossRef

Guo Q, Jin Z, Yuan Y, Liu R, Xu T, Wei H, Xu X, He S, Chen S, Shi Z, et al. New mechanisms of tumor-associated macrophages on promoting tumor progression: recent research advances and potential targets for tumor immunotherapy. J Immunol Res. 2016;2016:9720912.PubMedPubMedCentral

Rhee I. Diverse macrophages polarization in tumor microenvironment. Arch Pharm Res. 2016;39(11):1588–96.PubMedCrossRef

Weng Y-S, Tseng H-Y, Chen Y-A, Shen P-C, Al Haq AT, Chen L-M, Tung Y-C, Hsu H-L. MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer. Mol Cancer. 2019;18(1):42.PubMedPubMedCentralCrossRef

Ma B, Cheng H, Mu C, Geng G, Zhao T, Luo Q, Ma K, Chang R, Liu Q, Gao R, et al. The SIAH2-NRF1 axis spatially regulates tumor microenvironment remodeling for tumor progression. Nat Commun. 2019;10(1):1034.PubMedPubMedCentralCrossRef

Lee G-H, Yoo K-C, An Y, Lee H-J, Lee M, Uddin N, Kim M-J, Kim I-G, Suh Y, Lee S-J. FYN promotes mesenchymal phenotypes of basal type breast cancer cells through STAT5/NOTCH2 signaling node. Oncogene. 2018;37(14):1857–68.PubMedCrossRef

Hu K-F, Kong X-Y, Zhong M-C, Wan H-Y, Lin N, Pei X-H. Brucine inhibits bone metastasis of breast cancer cells by suppressing Jagged1/Notch1 signaling pathways. Chin J Integr Med. 2017;23(2):110–6.PubMedCrossRef

10.

Dickson BC, Mulligan AM, Zhang H, Lockwood G, O'Malley FP, Egan SE, Reedijk M. High-level JAG1 mRNA and protein predict poor outcome in breast cancer. Mod Pathol. 2007;20(6):685–93.PubMedCrossRef

11.

Liu H, Wang J, Liu Z, Wang L, Liu S, Zhang Q. Jagged1 modulated tumor-associated macrophage differentiation predicts poor prognosis in patients with invasive micropapillary carcinoma of the breast. Medicine. 2017;96(16):e6663.PubMedPubMedCentralCrossRef

12.

Lin X, Wang S, Sun M, Zhang C, Wei C, Yang C, Dou R, Liu Q, Xiong B. miR-195-5p/NOTCH2-mediated EMT modulates IL-4 secretion in colorectal cancer to affect M2-like TAM polarization. J Hematol Oncol. 2019;12(1):20.PubMedPubMedCentralCrossRef

13.

Liao XH, Wang JG, Li LY, Zhou DM, Ren KH, Jin YT, Lv L, Yu JG, Yang JY, Lu Q, et al. Long intergenic non-coding RNA APOC1P1-3 inhibits apoptosis by decreasing α-tubulin acetylation in breast cancer. Cell Death Dis. 2016;7(5):e2236.PubMedPubMedCentralCrossRef

14.

Calanca N, Paschoal AP, Munhoz ÉP, Galindo LT, Barbosa BM, Caldeira JRF, Oliveira RA, Cavalli LR, Rogatto SR, Rainho CA. The long non-coding RNA ANRASSF1 in the regulation of alternative protein-coding transcripts RASSF1A and RASSF1C in human breast cancer cells: implications to epigenetic therapy. Epigenetics. 2019;14(8):741–50.PubMedPubMedCentralCrossRef

15.

Tan B-S, Yang M-C, Singh S, Chou Y-C, Chen H-Y, Wang M-Y, Wang Y-C, Chen R-H. LncRNA NORAD is repressed by the YAP pathway and suppresses lung and breast cancer metastasis by sequestering S100P. Oncogene. 2019;38(28):5612–26.PubMedCrossRef

16.

Sun X, Luo L-H, Zhong K-Z, Li J-R. LncRNA PCAT29 suppresses cell proliferation, invasion, and migration in renal carcinoma by regulating FLOT1. Clin Surg Res Commun. 2018;2(3):35–42.CrossRef

17.

Hirose T, Yamazaki T, Nakagawa S. Molecular anatomy of the architectural NEAT1 noncoding RNA: the domains, interactors, and biogenesis pathway required to build phase-separated nuclear paraspeckles. Wiley interdiscip Rev RNA. 2019;10(6):e1545.PubMedCrossRef

18.

Lee JT, Bartolomei MS. X-inactivation, imprinting, and long noncoding RNAs in health and disease. Cell. 2013;152(6):1308–23.PubMedCrossRef

19.

Zhao J, Du P, Cui P, Qin Y, Ce H, Wu J, Zhou Z, Zhang W, Qin L, Huang G. LncRNA PVT1 promotes angiogenesis via activating the STAT3/VEGFA axis in gastric cancer. Oncogene. 2018;37(30):4094–109.PubMedCrossRef

20.

Wang P, Xue Y, Han Y, Lin L, Wu C, Xu S, Jiang Z, Xu J, Liu Q, Cao X. The STAT3-binding long noncoding RNA lnc-DC controls human dendritic cell differentiation. Science. 2014;344(6181):310–3.PubMedCrossRef

21.

Zhao L, Du X, Huang K, Zhang T, Teng Z, Niu W, Wang C, Xia G. Rac1 modulates the formation of primordial follicles by facilitating STAT3-directed Jagged1, GDF9 and BMP15 transcription in mice. Sci Rep. 2016;6:23972.PubMedPubMedCentralCrossRef

22.

Yang Z, Guo L, Liu D, Sun L, Chen H, Deng Q, Liu Y, Yu M, Ma Y, Guo N. Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop. Oncotarget. 2015;6(7):5072–87.

23.

Storch A, Burkhardt K, Ludolph AC, Schwarz J. Protective effects of riluzole on dopamine neurons: involvement of oxidative stress and cellular energy metabolism. J Neurochem. 2000;75(6):2259–69.PubMedCrossRef

24.

Flomerfelt FA, Gress RE. Analysis of Cell Proliferation and Homeostasis Using EdU Labeling. Methods Mol Biol. 2016;1323:211–20.PubMedPubMedCentralCrossRef

25.

Zeng M, Zhu L, Li L, Kang C. miR-378 suppresses the proliferation, migration and invasion of colon cancer cells by inhibiting SDAD1. Cell Mol Biol Lett. 2017;22:12.PubMedPubMedCentralCrossRef

26.

Jiang M, Qin C, Han M. Primary breast cancer induces pulmonary vascular hyperpermeability and promotes metastasis via the VEGF-PKC pathway. Mol Carcinog. 2016;55(6):1087–95.PubMedCrossRef

27.

Shukla CJ, McCorkindale AL, Gerhardinger C, Korthauer KD, Cabili MN, Shechner DM, Irizarry RA, Maass PG, Rinn JL. High-throughput identification of RNA nuclear enrichment sequences. EMBO J. 2018;37(6):e98452.PubMedPubMedCentralCrossRef

28.

Hu Y-P, Jin Y-P, Wu X-S, Yang Y, Li Y-S, Li H-F, Xiang S-S, Song X-L, Jiang L, Zhang Y-J, et al. LncRNA-HGBC stabilized by HuR promotes gallbladder cancer progression by regulating miR-502-3p/SET/AKT axis. Mol Cancer. 2019;18(1):167.PubMedPubMedCentralCrossRef

29.

Bierhoff H. Analysis of lncRNA-Protein Interactions by RNA-protein pull-down assays and RNA immunoprecipitation (RIP). Methods Mol Biol. 2018;1686:241–50.PubMedCrossRef

30.

Li X, Zhong W, Xu Y, Yu B, Liu H. Silencing of lncRNA LINC00514 inhibits the malignant behaviors of papillary thyroid cancer through miR-204-3p/CDC23 axis. Biochem Biophys Res Commun. 2019;508(4):1145–8.PubMedCrossRef

31.

Jung M, Ma Y, Iyer RP, DeLeon-Pennell KY, Yabluchanskiy A, Garrett MR, Lindsey ML. IL-10 improves cardiac remodeling after myocardial infarction by stimulating M2 macrophage polarization and fibroblast activation. Basic Res Cardiol. 2017;112(3):33.PubMedPubMedCentralCrossRef

32.

Peng M, Qiang L, Xu Y, Li C, Li T, Wang J. IL-35 ameliorates collagen-induced arthritis by promoting TNF-α-induced apoptosis of synovial fibroblasts and stimulating M2 macrophages polarization. FEBS J. 2019;286(10):1972–85.PubMedCrossRef

33.

Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer. 2014;14(11):736–46.PubMedCrossRef

34.

Banerjee K, Resat H. Constitutive activation of STAT3 in breast cancer cells: a review. Int J Cancer. 2016;138(11):2570–8.PubMedCrossRef

35.

Wu P, Wu D, Zhao L, Huang L, Shen G, Huang J, Chai Y. Prognostic role of STAT3 in solid tumors: a systematic review and meta-analysis. Oncotarget. 2016;7(15):19863–83.PubMedPubMedCentralCrossRef

36.

Wang T, Fahrmann JF, Lee H, Li Y-J, Tripathi SC, Yue C, Zhang C, Lifshitz V, Song J, Yuan Y, et al. JAK/STAT3-Regulated fatty acid β-oxidation is critical for breast cancer stem cell self-renewal and chemoresistance. Cell Metab. 2018;27(1):136–150.e135.PubMedCrossRef

37.

Chang R, Song L, Xu Y, Wu Y, Dai C, Wang X, Sun X, Hou Y, Li W, Zhan X, et al. Loss of Wwox drives metastasis in triple-negative breast cancer by JAK2/STAT3 axis. Nat Commun. 2018;9(1):3486.PubMedPubMedCentralCrossRef

38.

Li L, Tang P, Li S, Qin X, Yang H, Wu C, Liu Y. Notch signaling pathway networks in cancer metastasis: a new target for cancer therapy. Med Oncol. 2017;34(10):180.PubMedCrossRef

39.

Kontomanolis EN, Kalagasidou S, Pouliliou S, Anthoulaki X, Georgiou N, Papamanolis V, Fasoulakis ZN. The notch pathway in breast Cancer progression. ScientificWorldJournal. 2018;2018:2415489.PubMedPubMedCentralCrossRef

40.

Monsalve E, Pérez MA, Rubio A, Ruiz-Hidalgo MJ, Baladrón V, García-Ramírez JJ, Gómez JC, Laborda J, Díaz-Guerra MJM. Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity. J Immunol. 2006;176(9):5362–73.PubMedCrossRef

41.

Lin Y, Zhao J-L, Zheng Q-J, Jiang X, Tian J, Liang S-Q, Guo H-W, Qin H-Y, Liang Y-M, Han H. Notch signaling modulates macrophage polarization and phagocytosis through direct suppression of signal regulatory protein α expression. Front Immunol. 2018;9:1744.PubMedPubMedCentralCrossRef

42.

Derada Troletti C, Lopes Pinheiro MA, Charabati M, Gowing E, van Het Hof B, van der Pol SMA, Geerts D, Prat A, Fontijn RD, Unger WW, et al. Notch signaling is impaired during inflammation in a lunatic fringe-dependent manner. Brain Behav Immun. 2018;69:48–56.PubMedCrossRef

43.

Martínez VG, Rubio C, Martínez-Fernández M, Segovia C, López-Calderón F, Garín MI, Teijeira A, Munera-Maravilla E, Varas A, Sacedón R, et al. BMP4 induces M2 macrophage polarization and favors tumor progression in bladder Cancer. Clin Cancer Res. 2017;23(23):7388–99.PubMedCrossRef

44.

Su S, Liu Q, Chen J, Chen J, Chen F, He C, Huang D, Wu W, Lin L, Huang W, et al. A positive feedback loop between mesenchymal-like cancer cells and macrophages is essential to breast cancer metastasis. Cancer Cell. 2014;25(5):605–20.PubMedCrossRef

Title: Linc00514 promotes breast cancer metastasis and M2 polarization of tumor-associated macrophages via Jagged1-mediated notch signaling pathway
Authors: Sifeng Tao
Qiang Chen
Chen Lin
Haiying Dong
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Metastasis
Breast Cancer
Breast Cancer
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2020
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-020-01676-x

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