Browse > Article
http://dx.doi.org/10.5483/BMBRep.2019.52.3.308

Regulation of IL-6 signaling by miR-125a and let-7e in endothelial cells controls vasculogenic mimicry formation of breast cancer cells  

Park, Youngsook (Division of Biological Sciences, Sookmyung Women's University)
Kim, Jongmin (Division of Biological Sciences, Sookmyung Women's University)
Publication Information
BMB Reports / v.52, no.3, 2019 , pp. 214-219 More about this Journal
Abstract
The role of tumor-proximal factors in tumor plasticity during chemoresistance and metastasis following chemotherapy is well studied. However, the role of endothelial cell (EC) derived paracrine factors in tumor plasticity, their effect on chemotherapeutic outcome, and the mechanism by which these paracrine factors modulate the tumor microenvironment are not well understood. In this study, we report a novel mechanism by which endothelial miR-125a and let-7e-mediated regulation of interleukin-6 (IL-6) signaling can manipulate vasculogenic mimicry (VM) formation of MDA-MB-231 breast cancer cells. We found that endothelial IL-6 levels were significantly higher in response to cisplatin treatment, whereas levels of IL-6 upon cisplatin exposure remained unchanged in MDA-MB-231 breast cancer cells. We additionally found an inverse correlation between IL-6 and miR-125a/let-7e expression levels in cisplatin treated ECs. Interestingly, IL-6, IL-6 receptor (IL-6R), and signal transducer and activator of transcription 3 (STAT3) genes in the IL-6 pathway are closely regulated by miR-125a and let-7e, which directly target its 3' untranslated region. Functional analyses revealed that endothelial miR-125a and let-7e inhibit IL-6-induced adhesion of monocytes to ECs. Furthermore, conditioned medium from cisplatin treated ECs induced a significantly higher formation of VM in MDA-MB-231 breast cancer cells as compared to that from intact ECs; this effect of cisplatin treatment was abrogated by concurrent overexpression of miR-125a and let-7e. Overall, this study reveals a novel EC-tumor cell crosstalk mediated by the endothelial miR-125a/let-7e-IL-6 signaling axis, which might improve chemosensitivity and provide potential therapeutic targets for the treatment of cancer.
Keywords
Chemoresistance; Endothelial cell; IL-6 signaling; microRNA; Vasculogenic mimicry;
Citations & Related Records
Times Cited By KSCI : 3  (Citation Analysis)
연도 인용수 순위
1 Kirschmann DA, Seftor EA, Hardy KM, Seftor RE and Hendrix MJ (2012) Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications. Clin Cancer Res 18, 2726-2732   DOI
2 Cao Z, Bao M, Miele L, Sarkar FH, Wang Z and Zhou Q (2013) Tumour vasculogenic mimicry is associated with poor prognosis of human cancer patients: a systemic review and meta-analysis. Eur J Cancer 49, 3914-3923   DOI
3 Wagenblast E, Soto M, Gutierrez-Angel S et al (2015) A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature 520, 358-362   DOI
4 Hendrix MJ, Seftor EA, Hess AR and Seftor RE (2003) Vasculogenic mimicry and tumour-cell plasticity: lessons from melanoma. Nat Rev Cancer 3, 411-421   DOI
5 Williamson SC, Metcalf RL, Trapani F et al (2016) Vascu logenic mimicry in small cell lung cancer. Nat Commun 7, 13322   DOI
6 Bharti R, Dey G and Mandal M (2016) Cancer development, chemoresistance, epithelial to mesenchymal transition and stem cells: A snapshot of IL-6 mediated involvement. Cancer Lett 375, 51-61   DOI
7 Dijkgraaf EM, Welters MJ, Nortier JW, van der Burg SH and Kroep JR (2012) Interleukin-6/interleukin-6 receptor pathway as a new therapy target in epithelial ovarian cancer. Curr Pharm Des 18, 3816-3827   DOI
8 Rossi JF, Lu ZY, Jourdan M and Klein B (2015) Interleukin-6 as a therapeutic target. Clin Cancer Res 21, 1248-1257   DOI
9 Wang Y, Niu XL, Qu Y et al (2010) Autocrine production of interleukin-6 confers cisplatin and paclitaxel resistance in ovarian cancer cells. Cancer Lett 295, 110-123   DOI
10 Hong L, Sharp T, Khorsand B et al (2016) MicroRNA-200c Represses IL-6, IL-8, and CCL-5 Expression and Enhances Osteogenic Differentiation. PLoS One 11, e0160915   DOI
11 Chen SC, Chang YL, Wang DL and Cheng JJ (2006) Herbal remedy magnolol suppresses IL-6-induced STAT3 activation and gene expression in endothelial cells. Br J Pharmacol 148, 226-232   DOI
12 Zhang W, Shen X, Xie L, Chu M and Ma Y (2015) Micro-RNA-181b regulates endotoxin tolerance by targeting IL-6 in macrophage RAW264.7 cells. J Inflamm (Lond) 12, 18   DOI
13 Hunter CA and Jones SA (2015) IL-6 as a keystone cytokine in health and disease. Nat Immunol 16, 448-457   DOI
14 Kanda T and Takahashi T (2004) Interleukin-6 and cardiovascular diseases. Jpn Heart J 45, 183-193   DOI
15 Zhang GJ and Adachi I (1999) Serum interleukin-6 levels correlate to tumor progression and prognosis in metastatic breast carcinoma. Anticancer Res 19, 1427-1432
16 Nakashima J, Tachibana M, Horiguchi Y et al (2000) Serum interleukin 6 as a prognostic factor in patients with prostate cancer. Clin Cancer Res 6, 2702-2706
17 Seymour JF, Talpaz M, Cabanillas F, Wetzler M and Kurzrock R (1995) Serum interleukin-6 levels correlate with prognosis in diffuse large-cell lymphoma. J Clin Oncol 13, 575-582   DOI
18 Jansson MD and Lund AH (2012) MicroRNA and cancer. Mol Oncol 6, 590-610   DOI
19 Lee A, McLean D, Choi J, Kang H, Chang W and Kim J (2014) Therapeutic implications of microRNAs in pulmonary arterial hypertension. BMB Rep 47, 311-317   DOI
20 Kim J (2018) MicroRNAs as critical regulators of the endothelial to mesenchymal transition in vascular biology. BMB Rep 51, 65-72   DOI
21 Kang H, Park Y, Lee A et al (2017) Negative regulation of NOD1 mediated angiogenesis by PPARgamma-regulated miR-125a. Biochem Biophys Res Commun 482, 28-34   DOI
22 Zhu WY, Luo B, An JY et al (2014) Differential expression of miR-125a-5p and let-7e predicts the progression and prognosis of non-small cell lung cancer. Cancer Invest 32, 394-401   DOI
23 Li Z, Pan W, Shen Y et al (2018) IGF1/IGF1R and micro- RNA let-7e down-regulate each other and modulate proliferation and migration of colorectal cancer cells. Cell Cycle 17, 1212-1219   DOI
24 Shan Y, Liu Y, Zhao L, Liu B, Li Y and Jia L (2017) MicroRNA-33a and let-7e inhibit human colorectal cancer progression by targeting ST8SIA1. Int J Biochem Cell Biol 90, 48-58   DOI
25 Xiao M, Cai J, Cai L et al (2017) Let-7e sensitizes epithelial ovarian cancer to cisplatin through repressing DNA double strand break repair. J Ovarian Res 10, 24   DOI
26 Huang P, Mao LF, Zhang ZP et al (2018) Down-Regulated miR-125a-5p Promotes the Reprogramming of Glucose Metabolism and Cell Malignancy by Increasing Levels of CD147 in Thyroid Cancer. Thyroid 28, 613-623   DOI
27 Sun M, Guo S, Yao J et al (2019) MicroRNA-125a suppresses cell migration, invasion, and regulates hyaluronic acid synthase 1 expression by targeting signal transducers and activators of transcription 3 in renal cell carcinoma cells. J Cell Biochem 120, 1894-1902   DOI
28 Naidu S, Shi L, Magee P et al (2017) PDGFR-modulated miR-23b cluster and miR-125a-5p suppress lung tumorigenesis by targeting multiple components of KRAS and NF-kB pathways. Sci Rep 7, 15441   DOI
29 Lu G, Ma Y, Jia C et al (2017) Reduced miR-125a levels associated with poor survival of patients with hepatocellular cancer. Oncol Lett 14, 5952-5958
30 McCall MN, Kent OA, Yu J, Fox-Talbot K, Zaiman AL and Halushka MK (2011) MicroRNA profiling of diverse endothelial cell types. BMC Med Genomics 4, 78   DOI
31 Zhou W, Fong MY, Min Y et al (2014) Cancer-secreted miR-105 destroys vascular endothelial barriers to promote metastasis. Cancer Cell 25, 501-515   DOI
32 Zhang Y, Zhang Q, Gui L et al (2018) Let-7e inhibits TNF-alpha expression by targeting the methyl transferase EZH2 in DENV2-infected THP-1 cells. J Cell Physiol 233, 8605-8616   DOI
33 Schnegg CI, Yang MH, Ghosh SK and Hsu MY (2015) Induction of Vasculogenic Mimicry Overrides VEGF-A Silencing and Enriches Stem-like Cancer Cells in Melanoma. Cancer Res 75, 1682-1690   DOI
34 van der Schaft DW, Seftor RE, Seftor EA et al (2004) Effects of angiogenesis inhibitors on vascular network formation by human endothelial and melanoma cells. J Natl Cancer Inst 96, 1473-1477   DOI
35 Abdullah LN and Chow EK (2013) Mechanisms of chemoresistance in cancer stem cells. Clin Transl Med 2, 3   DOI
36 Holen KD and Saltz LB (2001) New therapies, new directions: advances in the systemic treatment of metastatic colorectal cancer. Lancet Oncol 2, 290-297   DOI
37 O'Reilly EA, Gubbins L, Sharma S et al (2015) The fate of chemoresistance in triple negative breast cancer (TNBC). BBA Clin 3, 257-275   DOI
38 Bleau AM, Hambardzumyan D, Ozawa T et al (2009) PTEN/PI3K/Akt pathway regulates the side population phenotype and ABCG2 activity in glioma tumor stem-like cells. Cell Stem Cell 4, 226-235   DOI
39 Deanfield JE, Halcox JP and Rabelink TJ (2007) Endothelial function and dysfunction: testing and clinical relevance. Circulation 115, 1285-1295   DOI
40 Hanahan D and Weinberg RA (2000) The hallmarks of cancer. Cell 100, 57-70   DOI
41 Lee A, Papangeli I, Park Y et al (2017) A PPARgammadependent miR-424/503-CD40 axis regulates inflammation mediated angiogenesis. Sci Rep 7, 2528   DOI
42 Jo HN, Kang H, Lee A et al (2017) Endothelial miR-26a regulates VEGF-Nogo-B receptor-mediated angiogenesis. BMB Rep 50, 384-389   DOI
43 Butler JM, Kobayashi H and Rafii S (2010) Instructive role of the vascular niche in promoting tumour growth and tissue repair by angiocrine factors. Nat Rev Cancer 10, 138-146   DOI
44 Gilbert LA and Hemann MT (2010) DNA damage-mediated induction of a chemoresistant niche. Cell 143, 355-366   DOI
45 Folberg R and Maniotis AJ (2004) Vasculogenic mimicry. APMIS 112, 508-525   DOI