View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector J Formos Med Assoc 2010;109(9):621–623 Contents lists available at ScienceDirect Volume 109 Number 9 September 2010 ISSN 0929 6646 Journal of the Journal of the Formosan Medical Association Formosan Medical Association Knockdown of miR-21 as a novel approach for leukemia therapy Fluoroquinolone prophylaxis—an Asian perspective Downregulation of S100A13 blocks FGF-1 release Application of head-up tilt table testing in children Formosan Medical Association Journal homepage: http://www.jfma-online.com Taipei, Taiwan News and Perspectives Knockdown of miR-21 as a Novel Approach for Leukemia Therapy Yimei Feng, Xinghua Chen,* Lei Gao MicroRNAs have remained in the spotlight since hematopoietic stem cells into hematopoietic their discovery. More and more studies have shown progenitor cells, giving rise to different lineages and that miRNAs play important roles in pathologic mature blood cells. Accordingly, the hematopoi- processes in solid tumors. Among them, micro- etic system becomes a good model for microRNA RNA-21 (miR-21) is one of the most prominent research. Hematopoiesis is governed by the con- miRNAs implicated in the genesis and progression comitant alteration in expression of several genes. of human cancer. Few studies, however, have fo- Given the ability of a single miRNA to control the cused on the mechanism of gene regulation by expression of several genes, it is proposed that miR-21 and its roles in hematopoiesis and leuke- miRNAs regulate the process of hematopoiesis.2 mogenesis. Because miR-21 is highly expressed in leukemic cells, here we present a hypothesis that knockdown of miR-21 may be a novel approach MiR-21 Fingerprints During for leukemia therapy. MiR-21 may also be a new Tumorigenesis, Including Leukemia diagnostic marker and therapeutic target for leukemia. MiR-21 is one of the most prominent miRNAs implicated in the genesis and progression of human cancer.3 MiR-21 is known by a number of MicroRNAs Regulate Hematopoiesis synonyms including hsa-mir-21, MIR21, miR-21, MIRN21 and miRNA21. In Homo sapiens, the MicroRNAs are a class of small (19–21 nucleotides) MIRN21 gene (DNA of premiR-21) is located on non-coding RNA molecules that have important chromosome 17q23.2 and is highly expressed in roles in many cellular pathways and whose different tumor types. MIRN21 has been involved aberrant expression appears to be a common fea- in promoting tumor growth, proliferation, anti- ture of malignancy.1 Hematopoiesis is sustained apoptosis, migration and response to gemcitabine- by continuous differentiation of multipotent based chemotherapy. The potential targets of ©2010 Elsevier & Formosan Medical Association ................................................... Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing, China. *Correspondence to: Professor Xinghua Chen, Department of Hematology, Xinqiao Hospital, The Third Military Medical University, Chongqing 400037, China. E-mail: [email protected] J Formos Med Assoc | 2010 • Vol 109 • No 9 621 Y. Feng, et al miR-21 include the programmed cell death protein Knockdown of MiR-21 as a Novel 4, reversion-inducing cysteine-rich protein with Approach for Leukemia Therapy kazal motifs, tropomyosin 1, sprouty 2, phospha- tase and tensin (PTEN) homolog and Nuclear We have raised a hypothesis that knockdown of factor IB (NFIB). More in-depth functional stud- miR-21 in leukemic cells can suppress the occur- ies with miR-21 are demonstrating that miR-21 rence and aggravation of leukemia. The main cause displays oncogenic activities and can be classed of residual leukemia and recurrence of leukemia as an oncomir in solid tumors. In contrast, the is the existence of leukemic stem cells. Therefore, role of miR-21 in the proliferation and differenti- a lentivirus vector of anti-miR-21 could be con- ation of hematologic neoplasm cells has at- structed and then transfected into leukemic stem tracted little attention. cells. In that way, after transfection with the anti- Chronic lymphocytic leukemia (CLL) is the miR-21 oligonucleotide, the expression of anti- most common leukemia among adults in Western apoptotic protein Bcl-2 in leukemia cells in the countries, and accounts for about 30% of all patient is decreased, while simultaneously tumor leukemia patients.4 Currently, little is known re- suppressor levels, such as PTEN, tropomyosin 1 garding the pathogenic factors initiating and ag- and programmed cell death protein 4, are in- gravating this disease. creased. Furthermore, the level of miR-21 could be CLL patients have been characterized by sig- used as a diagnostic marker. More information nificant overexpression of miR-21. Expression concerning the genesis, progression and progno- of miR-21 in patients with CLL is dramatically sis of leukemia could be gathered by monitoring higher (up to 10-fold) than that in CD19+ lym- the expression of miR-21. phocytes of normal people.5 Overexpression of miR-21 may, therefore, be one of the initiating events occurring in CLL. Gazon et al found that Knockdown of MiR-21 Inhibits the miR-21 was upregulated in acute myeloid Development of Cancer Cells leukemia (AML) patients with t (6;11).6 Jongen- Lavrencic et al reported that miR-21 is consistently Accumulating data is beginning to support the upregulated in AML, regardless of cytogenetic and attractive notion that sequence-specific inhibition molecular subtype.7 Ectopically raising miR-21 of a single oncomir, miR-21, can provide a novel expression in myeloma cells significantly re- therapeutic approach to modulate deregulated duced apoptosis levels. Loffler et al reasoned that proteins in cancer. For example, knockdown of miR-21 might contribute to the Stat3-dependent miR-21 in cultured glioblastoma cells triggered survival of myeloma cells.8 MiR-21, measured activation of caspases and lead to increased ap- by quantitative RT-PCR (reverse transcription- optotic cell death.11 Furthermore, knockdown of polymerase chain reaction), was also upregulated miR-21 in metastatic breast cancer MDA-MB-231 in T-cell leukemic (T-ALL) and T-cell lymphoma cells significantly reduced invasion and lung (ALCL) cell lines.9 There are two distinct molecu- metastasis.12 Knockdown of miR-21 in breast lar subtypes of diffuse large B cell lymphomas: cancer MCF-7 cells also lead to suppression of germinal center B cell-like and activated B cell- cell growth in vitro and tumor growth in a mouse like. Lawrie et al identified that miR-21 was more model.13 Additionally, knockdown of miR-21 in highly expressed in activated B cell-like cell lines hepatic cells increased expression of the PTEN compared with the germinal center B cell-like cell homolog tumor suppressor, and decreased tumor lines.10 Moreover, through multivariate analysis, cell proliferation, migration and invasion.14 In the expression of miR-21 was shown to be an in- short, these studies suggest that deletion or down- dependent prognostic indicator in diffuse large B regulation of miR-21 inhibits the development cell lymphomas.10 of cancer cells, thus leading to interference with 622 J Formos Med Assoc | 2010 • Vol 109 • No 9 MiR-21 and leukemia cancer initiation and progression. Given the pre- China (No. 30800496 and 30670890), and the vious findings demonstrating the result of miR- Chongqing Natural Science Foundation (No. 21 knockdown, similar outcomes could be seen 2008BB5293 and CSTC2009BA5011). following the knockdown of miR-21 in leukemic stem cells. References Conclusions 1. Lawrie CH. MicroRNAs and haematology: small molecules, big function. Br J Haematol 2007;137:503–12. Improving life quality and expectancy following 2. Yendamuri S, Calin GA. The role of microRNA in human diagnosis with leukemia has always been difficult leukemia: a review. Leukemia 2009;23:1257–63. 3. Selcuklu SD, Donoghue MTA, Spillane C. miR-21 as a key for oncologists, as the majority of chemothera- regulator of oncogenic processes. Biochem Soc Trans 2009; peutic regimens have significant side effects and 37:918–25. limited efficacy. Hematopoietic stem cell trans- 4. Calin GA, Pekarsky Y, Croce CM. The role of microRNA plantation may be considered in the treatment of and other non-coding RNA in the pathogenesis of chronic leukemia, but is costly in developing countries and lymphocytic leukemia. Best Pract Res Clin Haematol may lead to serious graft-versus-host disease and 2007;20:425–37. immunological rejection. Alternative approaches, 5. Fulci V, Chiaretti S, Goldoni M, et al. Quantitative tech- nologies establish a novel microRNA profile of chronic such as using antibodies or vaccines, are currently, lymphocytic leukemia. Blood 2007;109:4944–51. for the most part, experimental and in the early 6. Garzon R, Volinia S, Liu CG, et al. MicroRNA signatures as- stages of clinical use. The discovery that miR-21 sociated with cytogenetics and prognosis in acute myeloid is a key miRNA (oncomir) that is dysregulated leukemia. Blood 2008;111:3183–9. in many cancers indicates an important role of 7. Jongen-Lavrencic M, Sun SM, Dijkstra MK, et al. miRNAs in cancer. This finding starts a new era MicroRNA expression profiling in relation to the genetic of cancer investigations. heterogeneity of acute myeloid leukemia. Blood 2008; Determining how miR-21 is regulated and how 111:5078–85. 8. Loffler D, Brocke-Heidrich K, Pfeifer G, et al. Interleukin-6 it regulates downstream target genes will be a pre- dependent survival of multiple myeloma cells involves the requisite for rational design of cancer therapeutic Stat3-mediated induction of microRNA-21 through a highly strategies. Modulation of miR-21 expression can conserved enhancer. Blood 2007;110:1330–3. also be used as a diagnostic and prognostic marker 9. Lawrie CH, Saunders NJ, Soneji S, et al. MicroRNA ex- for cancer sufferers, leukemia patients in particular. pression in lymphocyte development and malignancy. Previously, little knowledge about the role of Leukemia 2008;22:1440–6.