Argonaute 2 promotes myeloma angiogenesis via microRNA dysregulation

Journal of Hematology & Oncology

Lijuan Chen²  Jianyong Li²  Jiaren Xu²  Qiguo Zhang¹  Ji Xu²  Rong Wang²  Xiaoyan Qu²  Wenjun Yu²  Shuang Wu² 

[1] Nanjing Gulou Hospital, Nanjing, China;Department of Hematology, First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, 300 Guangzhou Road, Nanjing 210029, China

关键词: Angiogenesis;    Myeloma;    miR-145;    miR-17/92 cluster;    let-7 family;    microRNA;    Argonaute 2;   

Others  :  801078
DOI  :  10.1186/1756-8722-7-40

 received in 2013-12-06, accepted in 2014-04-22,  发布年份 2014

【 摘 要 】

Background

Dysregulated microRNA (miRNA) expression contributes to cancer cell proliferation, apoptosis and angiogenesis. Angiogenesis is a hallmark of multiple myeloma (MM) development and progression. Argonaute 2 (AGO2) protein, a core component of the RNA-induced silencing complex (RISC), can directly bind to miRNAs and mediate target messenger RNA (mRNA) degradation. A previous study showed that AGO2 knockdown suppressed human umbilical vein endothelial cell (HUVEC) growth and tube formation. However, the roles and molecular mechanisms of AGO2-induced myeloma angiogenesis are not yet fully understood. The aim of this study was to characterize these roles and effects and their associated mechanisms.

Results

Supernatants from AGO2-overexpressing MM lines induced HUVEC migration and accelerated tube formation. Conversely, supernatants from AGO2-knockdown MM lines suppressed HUVEC cell migration and tube formation. Moreover, a chick chorioallantoic membrane (CAM) assay was used to demonstrate that AGO2 could drive neovessel formation in MM lines in vivo. Using an miRNA microarray, we observed that 25 miRNAs were upregulated and 7 were downregulated in response to AGO2. Most let-7 family members and 2 miR-17/92 cluster members (miR-17a and miR-92-1), all known pro-angiogenic miRNAs, were positively regulated by AGO2 whereas anti-angiogenic miRNAs such as miR-145 and miR-361 were negatively regulated by AGO2.

Conclusions

We conclude that AGO2 can drive neovessel formation in vitro and in vivo by dysregulating the expression of some angiogenic miRNAs. The pro-angiogenic miRNAs of the let-7 family and the miR-17/92 cluster, along with the anti-angiogenic miRNA miR-145, play crucial roles in AGO2-mediated angiogenesis by targeting angiogenesis-related genes.

【 授权许可】

   
2014 Wu et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

【 参考文献 】

• [1]Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC: Multiple myeloma. Lancet 2009, 374:324-339.
• [2]Mayani H: Hematopoietic and microenvironment alterations in bone marrow from patients with multiple myeloma. Leuk Res 2013, 37:228-229.
• [3]Manier S, Sacco A, Leleu X, Ghobrial IM, Roccaro AM: Bone marrow microenvironment in multiple myeloma progression. J Biomed Biotechnol 2012, 2012:157496.
• [4]Balakumaran A, Robey PG, Fedarko N, Landgren O: Bone marrow microenvironment in myelomagenesis: its potential role in early diagnosis. Expert Rev Mol Diagn 2010, 10:465-480.
• [5]Keeley EC, Mehrad B, Strieter RM: CXC chemokines in cancer angiogenesis and metastases. Adv Cancer Res 2010, 106:91-111.
• [6]Cocco C, Ferretti E, Airoldi I, Pistoia V: Cytokines as anti-angiogenic agents in haematological malignancies. Curr Cancer Drug Targets 2011, 11:997-1004.
• [7]Otjacques E, Binsfeld M, Noel A, Beguin Y, Cataldo D, Caers J: Biological aspects of angiogenesis in multiple myeloma. Int J Hematol 2011, 94:505-518.
• [8]Moehler T: Clinical experience with thalidomide and lenalidomide in multiple myeloma. Curr Cancer Drug Targets 2012, 12:372-390.
• [9]Tageja N: Lenalidomide - current understanding of mechanistic properties. Anticancer Agents Med Chem 2011, 11:315-326.
• [10]De Luisi A, Ferrucci A, Coluccia AM, Ria R, Moschetta M, de Luca E, Pieroni L, Maffia M, Urbani A, Di Pietro G, Guarini A, Ranieri G, Ditonno P, Berardi S, Caivano A, Basile A, Cascavilla N, Capalbo S, Quarta G, Dammacco F, Ribatti D, Vacca A: Lenalidomide restrains motility and overangiogenic potential of bone marrow endothelial cells in patients with active multiple myeloma. Clin Cancer Res 2011, 17:1935-1946.
• [11]Giatromanolaki A, Bai M, Margaritis D, Bourantas KL, Koukourakis MI, Sivridis E, Gatter KC: Hypoxia and activated VEGF/receptor pathway in multiple myeloma. Anticancer Res 2010, 30:2831-2836.
• [12]Guo D, Li C, Teng Q, Sun Z, Li Y, Zhang C: Notch1 overexpression promotes cell growth and tumor angiogenesis in myeloma. Neoplasma 2013, 60:33-40.
• [13]Harvey RD, Lonial S: PI3 kinase/AKT pathway as a therapeutic target in multiple myeloma. Future Oncol 2007, 3:639-647.
• [14]Nelson KM, Weiss GJ: MicroRNAs and cancer: past, present, and potential future. Mol Cancer Ther 2008, 7:3655-3660.
• [15]Poliseno L, Tuccoli A, Mariani L, Evangelista M, Citti L, Woods K, Mercatanti A, Hammond S, Rainaldi G: MicroRNAs modulate the angiogenic properties of HUVECs. Blood 2006, 108:3068-3071.
• [16]Otsuka M, Zheng M, Hayashi M, Lee JD, Yoshino O, Lin S, Han J: Impaired microRNA processing causes corpus luteum insufficiency and infertility in mice. J Clin Invest 2008, 118:1944-1954.
• [17]Kuehbacher A, Urbich C, Zeiher AM, Dimmeler S: Role of Dicer and Drosha for endothelial microRNA expression and angiogenesis. Circ Res 2007, 101:59-68.
• [18]Zou C, Xu Q, Mao F, Li D, Bian C, Liu LZ, Jiang Y, Chen X, Qi Y, Zhang X, Wang X, Sun Q, Kung HF, Lin MC, Dress A, Wardle F, Jiang BH, Lai L: MiR-145 inhibits tumor angiogenesis and growth by N-RAS and VEGF. Cell Cycle 2012, 11:2137-2145.
• [19]Chen L, Li C, Zhang R, Gao X, Qu X, Zhao M, Qiao C, Xu J, Li J: miR-17-92 cluster microRNAs confers tumorigenicity in multiple myeloma. Cancer Lett 2011, 309:62-70.
• [20]Dews M, Homayouni A, Yu D, Murphy D, Sevignani C, Wentzel E, Furth EE, Lee WM, Enders GH, Mendell JT, Thomas-Tikhonenko A: Augmentation of tumor angiogenesis by a Myc-activated microRNA cluster. Nat Genet 2006, 38:1060-1065.
• [21]Doebele C, Bonauer A, Fischer A, Scholz A, Reiss Y, Urbich C, Hofmann WK, Zeiher AM, Dimmeler S: Members of the microRNA-17-92 cluster exhibit a cell-intrinsic antiangiogenic function in endothelial cells. Blood 2010, 115:4944-4950.
• [22]Bonauer A, Carmona G, Iwasaki M, Mione M, Koyanagi M, Fischer A, Burchfield J, Fox H, Doebele C, Ohtani K, Chavakis E, Potente M, Tjwa M, Urbich C, Zeiher AM, Dimmeler S: MicroRNA-92a controls angiogenesis and functional recovery of ischemic tissues in mice. Science 2009, 324:1710-1713.
• [23]Cullen BR: Transcription and processing of human microRNA precursors. Mol cell 2004, 16:861-865.
• [24]Suarez Y, Fernandez-Hernando C, Yu J, Gerber SA, Harrison KD, Pober JS, Iruela-Arispe ML, Merkenschlager M, Sessa WC: Dicer-dependent endothelial microRNAs are necessary for postnatal angiogenesis. Proc Natl Acad Sci U S A 2008, 105:14082-14087.
• [25]Suarez Y, Fernandez-Hernando C, Pober JS, Sessa WC: Dicer dependent microRNAs regulate gene expression and functions in human endothelial cells. Circ Res 2007, 100:1164-1173.
• [26]Hock J, Meister G: The Argonaute protein family. Genome Biol 2008, 9:210. BioMed Central Full Text
• [27]Asai T, Suzuki Y, Matsushita S, Yonezawa S, Yokota J, Katanasaka Y, Ishida T, Dewa T, Kiwada H, Nango M, Oku N: Disappearance of the angiogenic potential of endothelial cells caused by Argonaute2 knockdown. Biochem Biophys Res Commun 2008, 368:243-248.
• [28]Hatanaka K, Shimizu K, Asai T, Oku N: [Antineovascular gene therapy by Ago2 knockdown]. Yakugaku Zasshi 2008, 128:1567-1575.
• [29]Zhou Y, Chen L, Barlogie B, Stephens O, Wu X, Williams DR, Cartron MA, van Rhee F, Nair B, Waheed S, Pineda-Roman M, Alsayed Y, Anaissie E, Shaughnessy JD Jr: High-risk myeloma is associated with global elevation of miRNAs and overexpression of EIF2C2/AGO2. Proc Natl Acad Sci U S A 2010, 107:7904-7909.
• [30]Pichiorri F, Suh SS, Ladetto M, Kuehl M, Palumbo T, Drandi D, Taccioli C, Zanesi N, Alder H, Hagan JP, Munker R, Volinia S, Boccadoro M, Garzon R, Palumbo A, Aqeilan RI, Croce CM: MicroRNAs regulate critical genes associated with multiple myeloma pathogenesis. Proc Natl Acad Sci U S A 2008, 105:12885-12890.
• [31]Gao X, Zhang R, Qu X, Zhao M, Zhang S, Wu H, Jianyong L, Chen L: MiR-15a, miR-16-1 and miR-17-92 cluster expression are linked to poor prognosis in multiple myeloma. Leuk Res 2012, 36:1505-1509.
• [32]Dhanabal M, Jeffers M, LaRochelle WJ, Lichenstein HS: Angioarrestin: a unique angiopoietin-related protein with anti-angiogenic properties. Biochem Biophys Res Commun 2005, 333:308-315.
• [33]Fan L, Wu Q, Xing X, Wei Y, Shao Z: MicroRNA-145 targets vascular endothelial growth factor and inhibits invasion and metastasis of osteosarcoma cells. Acta Biochim Biophys Sin (Shanghai) 2012, 44:407-414.
• [34]Shaughnessy JD Jr, Zhan F, Burington BE, Huang Y, Colla S, Hanamura I, Stewart JP, Kordsmeier B, Randolph C, Williams DR, Xiao Y, Xu H, Epstein J, Anaissie E, Krishna SG, Cottler-Fox M, Hollmig K, Mohiuddin A, Pineda-Roman M, Tricot G, van Rhee F, Sawyer J, Alsayed Y, Walker R, Zangari M, Crowley J, Barlogie B: A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1. Blood 2007, 109:2276-2284.
• [35]Li L, Yu C, Gao H, Li Y: Argonaute proteins: potential biomarkers for human colon cancer. BMC Cancer 2010, 10:38. BioMed Central Full Text
• [36]Adams BD, Claffey KP, White BA: Argonaute-2 expression is regulated by epidermal growth factor receptor and mitogen-activated protein kinase signaling and correlates with a transformed phenotype in breast cancer cells. Endocrinol 2009, 150:14-23.
• [37]Zhang X, Graves P, Zeng Y: Overexpression of human Argonaute2 inhibits cell and tumor growth. Biochim Biophys Acta 1830, 2012:2553-2561.
• [38]Hagiwara K, Kosaka N, Yoshioka Y, Takahashi RU, Takeshita F, Ochiya T: Stilbene derivatives promote Ago2-dependent tumour-suppressive microRNA activity. Sci Rep 2012, 2:314.
• [39]Lemaire M, Deleu S, De Bruyne E, Van Valckenborgh E, Menu E, Vanderkerken K: The microenvironment and molecular biology of the multiple myeloma tumor. Adv Cancer Res 2011, 110:19-42.
• [40]Ender C, Meister G: Argonaute proteins at a glance. J Cell Sci 2010, 123:1819-1823.
• [41]Landskroner-Eiger S, Moneke I, Sessa WC: miRNAs as modulators of angiogenesis. Cold Spring Harb Perspect Med 2013, 3:a006643.
• [42]Oike Y, Yasunaga K, Suda T: Angiopoietin-related/angiopoietin-like proteins regulate angiogenesis. Int J Hematol 2004, 80:21-28.
• [43]Kumar S, Witzig TE, Timm M, Haug J, Wellik L, Fonseca R, Greipp PR, Rajkumar SV: Expression of VEGF and its receptors by myeloma cells. Leukemia 2003, 17:2025-2031.
• [44]Sachdeva M, Mo YY: MicroRNA-145 suppresses cell invasion and metastasis by directly targeting mucin 1. Cancer Res 2010, 70:378-387.
• [45]Iorio MV, Ferracin M, Liu CG, Veronese A, Spizzo R, Sabbioni S, Magri E, Pedriali M, Fabbri M, Campiglio M, Ménard S, Palazzo JP, Rosenberg A, Musiani P, Volinia S, Nenci I, Calin GA, Querzoli P, Negrini M, Croce CM: MicroRNA gene expression deregulation in human breast cancer. Cancer Res 2005, 65:7065-7070.
• [46]Michael MZ, SM OC, van Holst Pellekaan NG, Young GP, James RJ: Reduced accumulation of specific microRNAs in colorectal neoplasia. Mol Cancer Res 2003, 1:882-891.
• [47]Zhu GQ, Tang YL, Li L, Zheng M, Jiang J, Li XY, Chen SX, Liang XH: Hypoxia inducible factor 1alpha and hypoxia inducible factor 2alpha play distinct and functionally overlapping roles in oral squamous cell carcinoma. Clin Cancer Res 2010, 16:4732-4741.
• [48]Augstein A, Poitz DM, Braun-Dullaeus RC, Strasser RH, Schmeisser A: Cell-specific and hypoxia-dependent regulation of human HIF-3alpha: inhibition of the expression of HIF target genes in vascular cells. Cell Mol Life Sci 2011, 68:2627-2642.
• [49]Sinning M, Letelier R, Rosas C, Fuenzalida M, Lemus D: Angiogenic potential of the cerebrospinal fluid (CSF) of patients with high-grade gliomas measured with the chick embryo chorioallantoic membrane assay (CAM). Biol Res 2012, 45:135-138.