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Molecular Cancer
Published in: Molecular Cancer 1/2019

Open Access 01-12-2019 | Tocilizumab | Research

MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer

Authors: Yueh-Shan Weng, Hong-Yu Tseng, Yen-An Chen, Pei-Chun Shen, Aushia Tanzih Al Haq, Li-Mei Chen, Yi-Chung Tung, Hsin-Ling Hsu

Published in: Molecular Cancer | Issue 1/2019

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Abstract

Background

Triple-negative breast cancer (TNBC) is a poor prognostic breast cancer with the highest mutations and limited therapeutic choices. Cytokine networking between cancer cells and the tumor microenvironment (TME) maintains the self-renewing subpopulation of breast cancer stem cells (BCSCs) that mediate tumor heterogeneity, resistance and recurrence. Immunotherapy of those factors combined with targeted therapy or chemoagents may advantage TNBC treatment.

Results

We found that the oncogene Multiple Copies in T-cell Malignancy 1 (MCT-1/MCTS1) expression is a new poor-prognosis marker in patients with aggressive breast cancers. Overexpressing MCT-1 perturbed the oncogenic breast epithelial acini morphogenesis and stimulated epithelial-mesenchymal transition and matrix metalloproteinase activation in invasive TNBC cells, which were repressed after MCT-1 gene silencing. As mammary tumor progression was promoted by oncogenic MCT-1 activation, tumor-promoting M2 macrophages were enriched in TME, whereas M2 macrophages were decreased and tumor-suppressive M1 macrophages were increased as the tumor was repressed via MCT-1 knockdown. MCT-1 stimulated interleukin-6 (IL-6) secretion that promoted monocytic THP-1 polarization into M2-like macrophages to increase TNBC cell invasiveness. In addition, MCT-1 elevated the soluble IL-6 receptor levels, and thus, IL-6R antibodies antagonized the effect of MCT-1 on promoting M2-like polarization and cancer cell invasion. Notably, MCT-1 increased the features of BCSCs, which were further advanced by IL-6 but prevented by tocilizumab, a humanized IL-6R antibody, thus MCT-1 knockdown and tocilizumab synergistically inhibited TNBC stemness. Tumor suppressor miR-34a was induced upon MCT-1 knockdown that inhibited IL-6R expression and activated M1 polarization.

Conclusions

The MCT-1 pathway is a novel and promising therapeutic target for TNBC.
Appendix
Available only for authorised users
Literature
1.
Pradella D, Naro C, Sette C, Ghigna C. EMT and stemness: flexible processes tuned by alternative splicing in development and cancer progression. Mol Cancer. 2017;16(8).
2.
Lopez-Soto A, Gonzalez S, Smyth MJ, Galluzzi L. Control of metastasis by NK cells. Cancer Cell. 2017;32:135–54.CrossRef
3.
Solinas G, Schiarea S, Liguori M, Fabbri M, Pesce S, Zammataro L, Pasqualini F, Nebuloni M, Chiabrando C, Mantovani A, Allavena P. Tumor-conditioned macrophages secrete migration-stimulating factor: a new marker for M2-polarization, influencing tumor cell motility. J Immunol. 2010;185:642–52.CrossRef
4.
Solinas G, Germano G, Mantovani A, Allavena P. Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol. 2009;86:1065–73.CrossRef
5.
Santoni M, Romagnoli E, Saladino T, Foghini L, Guarino S, Capponi M, Giannini M, Cognigni PD, Ferrara G, Battelli N. Triple negative breast cancer: key role of tumor-associated macrophages in regulating the activity of anti-PD-1/PD-L1 agents. Biochim Biophys Acta. 2018;1869:78–84.
6.
Goswami KK, Ghosh T, Ghosh S, Sarkar M, Bose A, Baral R. Tumor promoting role of anti-tumor macrophages in tumor microenvironment. Cell Immunol. 2017;316:1–10.CrossRef
7.
Kampan NC, Xiang SD, McNally OM, Stephens AN, Quinn MA, Plebanski M. Immunotherapeutic Interleukin-6 or Interleukin-6 receptor blockade in cancer: challenges and opportunities. Curr Med Chem. 2017.
8.
Rokavec M, Oner MG, Li H, Jackstadt R, Jiang L, Lodygin D, Kaller M, Horst D, Ziegler PK, Schwitalla S, et al. IL-6R/STAT3/miR-34a feedback loop promotes EMT-mediated colorectal cancer invasion and metastasis. J Clin Invest. 2014;124:1853–67.CrossRef
9.
Noman AS, Uddin M, Chowdhury AA, Nayeem MJ, Raihan Z, Rashid MI, Azad AK, Rahman ML, Barua D, Sultana A, et al. Serum sonic hedgehog (SHH) and interleukin-(IL-6) as dual prognostic biomarkers in progressive metastatic breast cancer. Sci Rep. 2017;7:1796.CrossRef
10.
Heo TH, Wahler J, Suh N. Potential therapeutic implications of IL-6/IL-6R/gp130-targeting agents in breast cancer. Oncotarget. 2016;7:15460–73.PubMedPubMedCentral
11.
Kitamura H, Ohno Y, Toyoshima Y, Ohtake J, Homma S, Kawamura H, Takahashi N, Taketomi A. Interleukin-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy. Cancer Sci. 2017;108:1947–52.CrossRef
12.
Guo C, Chen Y, Gao W, Chang A, Ye Y, Shen W, Luo Y, Yang S, Sun P, Xiang R, Li N. Liposomal nanoparticles carrying anti-IL6R antibody to the tumour microenvironment inhibit metastasis in two molecular subtypes of breast Cancer mouse models. Theranostics. 2017;7:775–88.CrossRef
13.
Schleich S, Strassburger K, Janiesch PC, Koledachkina T, Miller KK, Haneke K, Cheng YS, Kuechler K, Stoecklin G, Duncan KE, Teleman AA. DENR-MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth. Nature. 2014;512:208–12.CrossRef
14.
Skabkin MA, Skabkina OV, Dhote V, Komar AA, Hellen CU, Pestova TV. Activities of Ligatin and MCT-1/DENR in eukaryotic translation initiation and ribosomal recycling. Genes Dev. 2010;24:1787–801.CrossRef
15.
Lomakin IB, Stolboushkina EA, Vaidya AT, Zhao C, Garber MB, Dmitriev SE, Steitz TA. Crystal structure of the human ribosome in complex with DENR-MCT-1. Cell Rep. 2017;20:521–8.CrossRef
16.
Weisser M, Schafer T, Leibundgut M, Bohringer D, Aylett CHS, Ban N. Structural and functional insights into human re-initiation complexes. Mol Cell. 2017;67:447–456 e447.CrossRef
17.
Shih HJ, Chu KL, Wu MH, Wu PH, Chang WW, Chu JS, Wang LH, Takeuchi H, Ouchi T, Hsu HL. The involvement of MCT-1 oncoprotein in inducing mitotic catastrophe and nuclear abnormalities. Cell Cycle. 2012;11:934–52.CrossRef
18.
Wu MH, Chen YA, Chen HH, Chang KW, Chang IS, Wang LH, Hsu HL. MCT-1 expression and PTEN deficiency synergistically promote neoplastic multinucleation through the Src/p190B signaling activation. Oncogene. 2014;33:5109–20.CrossRef
19.
Hsu HL, Choy CO, Kasiappan R, Shih HJ, Sawyer JR, Shu CL, Chu KL, Chen YR, Hsu HF, Gartenhaus RB. MCT-1 oncogene downregulates p53 and destabilizes genome structure in the response to DNA double-strand damage. DNA Repair (Amst). 2007;6:1319–32.CrossRef
20.
Kasiappan R, Shih HJ, Chu KL, Chen WT, Liu HP, Huang SF, Choy CO, Shu CL, Din R, Chu JS, Hsu HL. Loss of p53 and MCT-1 overexpression synergistically promote chromosome instability and tumorigenicity. Mol Cancer Res. 2009;7:536–48.CrossRef
21.
Kasiappan R, Shih HJ, Wu MH, Choy C, Lin TD, Chen L, Hsu HL. The antagonism between MCT-1 and p53 affects the tumorigenic outcomes. Mol Cancer. 2010;9:311.CrossRef
22.
Shih HJ, Chen HH, Chen YA, Wu MH, Liou GG, Chang WW, Chen L, Wang LH, Hsu HL. Targeting MCT-1 oncogene inhibits Shc pathway and xenograft tumorigenicity. Oncotarget. 2012;3:1401–15.CrossRef
23.
Tseng HY, Chen YA, Jen J, Shen PC, Chen LM, Lin TD, Wang YC, Hsu HL. Oncogenic MCT-1 activation promotes YY1-EGFR-MnSOD signaling and tumor progression. Oncogenesis. 2017;6:e313.CrossRef
24.
Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, Szallasi Z. An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat. 2010;123:725–31.CrossRef
25.
Debnath J, Muthuswamy SK, Brugge JS. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods. 2003;30:256–68.CrossRef
26.
Zhang Y, Yan W, Chen X. Mutant p53 disrupts MCF-10A cell polarity in three-dimensional culture via epithelial-to-mesenchymal transitions. J Biol Chem. 2011;286:16218–28.CrossRef
27.
Chan SH, Huang WC, Chang JW, Chang KJ, Kuo WH, Wang MY, Lin KY, Uen YH, Hou MF, Lin CM, et al. MicroRNA-149 targets GIT1 to suppress integrin signaling and breast cancer metastasis. Oncogene. 2014;33:4496–507.CrossRef
28.
Fu XL, Duan W, Su CY, Mao FY, Lv YP, Teng YS, Yu PW, Zhuang Y, Zhao YL. Interleukin 6 induces M2 macrophage differentiation by STAT3 activation that correlates with gastric cancer progression. Cancer Immunol Immunother. 2017;66:1597–608.CrossRef
29.
Jones SA, Rose-John S. The role of soluble receptors in cytokine biology: the agonistic properties of the sIL-6R/IL-6 complex. Biochim Biophys Acta. 2002;1592:251–63.CrossRef
30.
Lazzaro L, Tonkin BA, Poulton IJ, McGregor NE, Ferlin W, Sims NA. IL-6 trans-signalling mediates trabecular, but not cortical, bone loss after ovariectomy. Bone. 2018;112:120–7.CrossRef
31.
Genard G, Lucas S, Michiels C. Reprogramming of tumor-associated macrophages with anticancer therapies: radiotherapy versus chemo- and immunotherapies. Front Immunol. 2017;8:828.CrossRef
32.
Peng D, Tanikawa T, Li W, Zhao L, Vatan L, Szeliga W, Wan S, Wei S, Wang Y, Liu Y, et al. Myeloid-derived suppressor cells endow stem-like qualities to breast Cancer cells through IL6/STAT3 and NO/NOTCH cross-talk signaling. Cancer Res. 2016;76:3156–65.CrossRef
33.
Rupaimoole R, Slack FJ. MicroRNA therapeutics: towards a new era for the management of cancer and other diseases. Nat Rev Drug Discov. 2017;16:203–22.CrossRef
34.
Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL, Fell HP, Ferree S, George RD, Grogan T, et al. Direct multiplexed measurement of gene expression with color-coded probe pairs. Nat Biotechnol. 2008;26:317–25.CrossRef
35.
Kantono M, Guo B. Inflammasomes and Cancer: the dynamic role of the Inflammasome in tumor development. Front Immunol. 2017;8:1132.CrossRef
36.
Li Z, Qiu Y, Lu W, Jiang Y, Wang J. Immunotherapeutic interventions of triple negative breast Cancer. J Transl Med. 2018;16:147.CrossRef
37.
Solary E. When monocyte life hangs by a thread. Blood. 2012;119:2699–700.CrossRef
38.
Duluc D, Delneste Y, Tan F, Moles MP, Grimaud L, Lenoir J, Preisser L, Anegon I, Catala L, Ifrah N, et al. Tumor-associated leukemia inhibitory factor and IL-6 skew monocyte differentiation into tumor-associated macrophage-like cells. Blood. 2007;110:4319–30.CrossRef
39.
Chen K, Huang YH, Chen JL. Understanding and targeting cancer stem cells: therapeutic implications and challenges. Acta Pharmacol Sin. 2013;34:732–40.CrossRef
40.
Guo Y, Xu F, Lu T, Duan Z, Zhang Z. Interleukin-6 signaling pathway in targeted therapy for cancer. Cancer Treat Rev. 2012;38:904–10.CrossRef
41.
Chin AR, Wang SE. Cytokines driving breast cancer stemness. Mol Cell Endocrinol. 2014;382:598–602.CrossRef
42.
Korkaya H, Kim GI, Davis A, Malik F, Henry NL, Ithimakin S, Quraishi AA, Tawakkol N, D'Angelo R, Paulson AK, et al. Activation of an IL6 inflammatory loop mediates trastuzumab resistance in HER2+ breast cancer by expanding the cancer stem cell population. Mol Cell. 2012;47:570–84.CrossRef
43.
Fisher DT, Appenheimer MM, Evans SS. The two faces of IL-6 in the tumor microenvironment. Semin Immunol. 2014;26:38–47.CrossRef
44.
Wang N, Liang H, Zen K. Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol. 2014;5:614.PubMedPubMedCentral
45.
Lin J, He Y, Chen J, Zeng Z, Yang B, Ou Q. A critical role of transcription factor YY1 in rheumatoid arthritis by regulation of interleukin-6. J Autoimmun. 2017;77:67–75.CrossRef
46.
Alberti C, Pinciroli P, Valeri B, Ferri R, Ditto A, Umezawa K, Sensi M, Canevari S, Tomassetti A. Ligand-dependent EGFR activation induces the co-expression of IL-6 and PAI-1 via the NFkB pathway in advanced-stage epithelial ovarian cancer. Oncogene. 2012;31:4139–49.CrossRef
47.
Cortez MA, Ivan C, Valdecanas D, Wang X, Peltier HJ, Ye Y, Araujo L, Carbone DP, Shilo K, Giri DK, et al. PDL1 regulation by p53 via miR-34. J Natl Cancer Inst. 2016;108.
48.
Wang X, Li J, Dong K, Lin F, Long M, Ouyang Y, Wei J, Chen X, Weng Y, He T, Zhang H. Tumor suppressor miR-34a targets PD-L1 and functions as a potential immunotherapeutic target in acute myeloid leukemia. Cell Signal. 2015;27:443–52.CrossRef
49.
Liu C, Kelnar K, Liu B, Chen X, Calhoun-Davis T, Li H, Patrawala L, Yan H, Jeter C, Honorio S, et al. The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44. Nat Med. 2011;17:211–5.CrossRef
50.
Siemens H, Jackstadt R, Hunten S, Kaller M, Menssen A, Gotz U, Hermeking H. miR-34 and SNAIL form a double-negative feedback loop to regulate epithelial-mesenchymal transitions. Cell Cycle. 2011;10:4256–71.CrossRef
51.
Hahn S, Jackstadt R, Siemens H, Hunten S, Hermeking H. SNAIL and miR-34a feed-forward regulation of ZNF281/ZBP99 promotes epithelial-mesenchymal transition. EMBO J. 2013;32:3079–95.CrossRef
52.
Schupp J, Krebs FK, Zimmer N, Trzeciak E, Schuppan D, Tuettenberg A. Targeting myeloid cells in the tumor sustaining microenvironment. Cell Immunol. 2017.
53.
Self-Fordham JB, Naqvi AR, Uttamani JR, Kulkarni V, Nares S. MicroRNA: dynamic regulators of macrophage polarization and plasticity. Front Immunol. 2017;8:1062.CrossRef
Metadata
Title
MCT-1/miR-34a/IL-6/IL-6R signaling axis promotes EMT progression, cancer stemness and M2 macrophage polarization in triple-negative breast cancer
Authors
Yueh-Shan Weng
Hong-Yu Tseng
Yen-An Chen
Pei-Chun Shen
Aushia Tanzih Al Haq
Li-Mei Chen
Yi-Chung Tung
Hsin-Ling Hsu
Publication date
01-12-2019
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2019
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-019-0988-0

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