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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2017

Open Access 01-12-2017 | Research

MiR21 sensitized B-lymphoma cells to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells

Authors: Zhong Zheng, Peng-Peng Xu, Li Wang, Hui-Jin Zhao, Xiang-Qin Weng, Hui-Juan Zhong, Bin Qu, Jie Xiong, Yan Zhao, Xue-Feng Wang, Anne Janin, Wei-Li Zhao

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

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Abstract

Background

MicroRNAs (miRs) are involved in tumor progression by regulating tumor cells and tumor microenvironment. MiR21 is overexpressed in diffuse large B-cell lymphoma (DLBCL) and its biological impact on tumor microenvironment remains unclear.

Methods

MiR21 was assessed by quantitative RT-PCR in patients with newly diagnosed DLBCL. The mechanism of action of miR21 on lymphoma progression and tumor angiogenesis was examined in vitro in B-lymphoma cell lines and in vivo in a murine xenograft model.

Results

Serum miR21 was significantly elevated in patients and associated with advanced disease stage, International Prognostic Index indicating intermediate-high and high-risk, and increased tumor angiogenesis. When co-cultured with immune cells and endothelial cells, miR21-overexpressing B-lymphoma cells were resistant to chemotherapeutic agents, but sensitive to Bcl-2 inhibitor ABT-199, irrespective of Bcl-2 expression on lymphoma cells. In both co-culture systems of Bcl-2positive and Bcl-2negative B-lymphoma cells, miR21 induced inducible co-stimulator (ICOS) expression on regulatory T (Treg) cells. Through crosstalking with Treg cells by ICOS ligand (ICOSL), endothelial cells were activated, resulting in stimulation of Bcl-2 expression and vessel formation. ABT-199 directly targeted Bcl-2 on endothelial cells, induced endothelial cell apoptosis and inhibited tumor angiogenesis. In a murine xenograft model established with subcutaneous injection of B-lymphoma cells, ABT-199 particularly retarded the growth of miR21-overexpressing tumors, consistent with the induction of endothelial cell apoptosis and inhibition of tumor angiogenesis.

Conclusions

As a serum oncogenic biomarker of B-cell lymphoma, miR21 indicated B-lymphoma cell sensitivity to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells.
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Literature
1.
Sehn LH, Gascoyne RD. Diffuse large B-cell lymphoma: optimizing outcome in the context of clinical and biologic heterogeneity. Blood. 2015;125(1):22–32.CrossRefPubMed
2.
Souers AJ, Leverson JD, Boghaert ER, Ackler SL, Catron ND, Chen J, Dayton BD, Ding H, Enschede SH, Fairbrother WJ, et al. ABT-199, a potent and selective BCL-2 inhibitor, achieves antitumor activity while sparing platelets. Nat Med. 2013;19(2):202–8.CrossRefPubMed
3.
Vandenberg CJ, Cory S. ABT-199, a new Bcl-2-specific BH3 mimetic, has in vivo efficacy against aggressive Myc-driven mouse lymphomas without provoking thrombocytopenia. Blood. 2013;121(12):2285–8.CrossRefPubMedPubMedCentral
4.
5.
Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011;10(6):417–27.CrossRefPubMed
6.
Motz GT, Coukos G. The parallel lives of angiogenesis and immunosuppression: cancer and other tales. Nat Rev Immunol. 2011;11(10):702–11.CrossRefPubMed
7.
8.
9.
Scott DW, Gascoyne RD. The tumour microenvironment in B cell lymphomas. Nat Rev Cancer. 2014;14(8):517–34.CrossRefPubMed
10.
Dianzani C, Minelli R, Mesturini R, Chiocchetti A, Barrera G, Boscolo S, Sarasso C, Gigliotti CL, Sblattero D, Yagi J, et al. B7h triggering inhibits umbilical vascular endothelial cell adhesiveness to tumor cell lines and polymorphonuclear cells. J Immunol. 2010;185(7):3970–9.CrossRefPubMed
11.
Chiron D, Dousset C, Brosseau C, Touzeau C, Maiga S, Moreau P, Pellat-Deceunynck C, Le Gouill S, Amiot M. Biological rational for sequential targeting of Bruton tyrosine kinase and Bcl-2 to overcome CD40-induced ABT-199 resistance in mantle cell lymphoma. Oncotarget. 2015;6(11):8750–9.CrossRefPubMedPubMedCentral
12.
Lee D, Shin C. MicroRNA-target interactions: new insights from genome-wide approaches. Ann N Y Acad Sci. 2012;1271:118–128.
13.
14.
Cheng CJ, Bahal R, Babar IA, Pincus Z, Barrera F, Liu C, Svoronos A, Braddock DT, Glazer PM, Engelman DM, et al. MicroRNA silencing for cancer therapy targeted to the tumour microenvironment. Nature. 2015;518(7537):107–10.CrossRefPubMed
15.
Dong J, Zhao YP, Zhou L, Zhang TP, Chen G. Bcl-2 upregulation induced by miR-21 via a direct interaction is associated with apoptosis and chemoresistance in MIA PaCa-2 pancreatic cancer cells. Arch Med Res. 2011;42(1):8–14.CrossRefPubMed
16.
Fang C, Zhu DX, Dong HJ, Zhou ZJ, Wang YH, Liu L, Fan L, Miao KR, Liu P, Xu W, et al. Serum microRNAs are promising novel biomarkers for diffuse large B cell lymphoma. Ann Hematol. 2012;91(4):553–9.CrossRefPubMed
17.
Lawrie CH, Gal S, Dunlop HM, Pushkaran B, Liggins AP, Pulford K, Banham AH, Pezzella F, Boultwood J, Wainscoat JS, et al. Detection of elevated levels of tumour-associated microRNAs in serum of patients with diffuse large B-cell lymphoma. Br J Haematol. 2008;141(5):672–5.CrossRefPubMed
18.
Zheng Z, Cheng S, Wu W, Wang L, Zhao Y, Shen Y, Janin A, Zhao WL. c-FLIP is involved in tumor progression of peripheral T-cell lymphoma and targeted by histone deacetylase inhibitors. J Hematol Oncol. 2014;7:88.CrossRefPubMedPubMedCentral
19.
Dong LH, Cheng S, Zheng Z, Wang L, Shen Y, Shen ZX, Chen SJ, Zhao WL. Histone deacetylase inhibitor potentiated the ability of MTOR inhibitor to induce autophagic cell death in Burkitt leukemia/lymphoma. J Hematol Oncol. 2013;6:53.CrossRefPubMedPubMedCentral
20.
Berger AC, Feldman AL, Gnant MF, Kruger EA, Sim BK, Hewitt S, Figg WD, Alexander HR, Libutti SK. The angiogenesis inhibitor, endostatin, does not affect murine cutaneous wound healing. J Surg Res. 2000;91(1):26–31.CrossRefPubMed
21.
Deng J, Carlson N, Takeyama K, Dal Cin P, Shipp M, Letai A. BH3 profiling identifies three distinct classes of apoptotic blocks to predict response to ABT-737 and conventional chemotherapeutic agents. Cancer Cell. 2007;12(2):171–85.CrossRefPubMed
22.
Jiang LH, Ge MH, Hou XX, Cao J, Hu SS, Lu XX, Han J, Wu YC, Liu X, Zhu X, et al. miR-21 regulates tumor progression through the miR-21-PDCD4-Stat3 pathway in human salivary adenoid cystic carcinoma. Lab Invest. 2015;95(12):1398–408.CrossRefPubMed
23.
Lawrie CH. MicroRNAs and lymphomagenesis: a functional review. Br J Haematol. 2013;160(5):571–81.CrossRefPubMed
24.
Baraniskin A, Kuhnhenn J, Schlegel U, Chan A, Deckert M, Gold R, Maghnouj A, Zollner H, Reinacher-Schick A, Schmiegel W, et al. Identification of microRNAs in the cerebrospinal fluid as marker for primary diffuse large B-cell lymphoma of the central nervous system. Blood. 2011;117(11):3140–6.CrossRefPubMed
25.
Medina PP, Nolde M, Slack FJ. OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma. Nature. 2010;467(7311):86–90.CrossRefPubMed
26.
Li J, Fu R, Yang L, Tu W. miR-21 expression predicts prognosis in diffuse large B-cell lymphoma. Int J Clin Exp Pathol. 2015;8(11):15019–24.PubMedPubMedCentral
27.
Chen W, Wang H, Chen H, Liu S, Lu H, Kong D, Huang X, Kong Q, Lu Z. Clinical significance and detection of microRNA-21 in serum of patients with diffuse large B-cell lymphoma in Chinese population. Eur J Haematol. 2014;92(5):407–12.CrossRefPubMed
28.
Chen B, Chen X, Wu X, Wang X, Wang Y, Lin TY, Kurata J, Wu J, Vonderfecht S, Sun G, et al. Disruption of microRNA-21 by TALEN leads to diminished cell transformation and increased expression of cell-environment interaction genes. Cancer Lett. 2015;356(2 Pt B):506–16.CrossRefPubMed
29.
An G, Acharya C, Feng X, Wen K, Zhong M, Zhang L, Munshi NC, Qiu L, Tai YT, Anderson KC. Osteoclasts promote immune suppressive microenvironment in multiple myeloma: therapeutic implication. Blood. 2016;128(12):1590–603.CrossRefPubMed
30.
Wang X, Li C, Ju S, Wang Y, Wang H, Zhong R. Myeloma cell adhesion to bone marrow stromal cells confers drug resistance by microRNA-21 up-regulation. Leuk Lymphoma. 2011;52(10):1991–8.CrossRefPubMed
31.
De Mattos-Arruda L, Bottai G, Nuciforo PG, Di Tommaso L, Giovannetti E, Peg V, Losurdo A, Perez-Garcia J, Masci G, Corsi F, et al. MicroRNA-21 links epithelial-to-mesenchymal transition and inflammatory signals to confer resistance to neoadjuvant trastuzumab and chemotherapy in HER2-positive breast cancer patients. Oncotarget. 2015;6(35):37269–80.PubMedPubMedCentral
32.
33.
Ito T, Hanabuchi S, Wang YH, Park WR, Arima K, Bover L, Qin FX, Gilliet M, Liu YJ. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity. 2008;28(6):870–80.CrossRefPubMedPubMedCentral
34.
Lee HJ, Kim SN, Jeon MS, Yi T, Song SU. ICOSL expression in human bone marrow-derived mesenchymal stem cells promotes induction of regulatory T cells. Sci Rep. 2017;7:44486.CrossRefPubMedPubMedCentral
35.
Busse M, Krech M, Meyer-Bahlburg A, Hennig C, Hansen G. ICOS mediates the generation and function of CD4 + CD25 + Foxp3+ regulatory T cells conveying respiratory tolerance. J Immunol. 2012;189(4):1975–82.CrossRefPubMed
36.
Wu D, Tang R, Qi Q, Zhou X, Zhou H, Mao Y, Li R, Liu C, Wang W, Hua D, et al. Five functional polymorphisms of B7/CD28 co-signaling molecules alter susceptibility to colorectal cancer. Cell Immunol. 2015;293(1):41–8.CrossRefPubMed
37.
Le KS, Thibult ML, Just-Landi S, Pastor S, Gondois-Rey F, Granjeaud S, Broussais F, Bouabdallah R, Colisson R, Caux C, et al. Follicular B lymphomas generate regulatory T cells via the ICOS/ICOSL pathway and Are susceptible to treatment by anti-ICOS/ICOSL therapy. Cancer Res. 2016;76(16):4648–60.CrossRefPubMed
38.
Go H, Jang JY, Kim PJ, Kim YG, Nam SJ, Paik JH, Kim TM, Heo DS, Kim CW, Jeon YK. MicroRNA-21 plays an oncogenic role by targeting FOXO1 and activating the PI3K/AKT pathway in diffuse large B-cell lymphoma. Oncotarget. 2015;6(17):15035–49.CrossRefPubMedPubMedCentral
Metadata
Title
MiR21 sensitized B-lymphoma cells to ABT-199 via ICOS/ICOSL-mediated interaction of Treg cells with endothelial cells
Authors
Zhong Zheng
Peng-Peng Xu
Li Wang
Hui-Jin Zhao
Xiang-Qin Weng
Hui-Juan Zhong
Bin Qu
Jie Xiong
Yan Zhao
Xue-Feng Wang
Anne Janin
Wei-Li Zhao
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-017-0551-z

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