miR-203 inhibits proliferation and self-renewal of leukemia stem cells by targeting survivin and Bmi-1

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Abstract

Drug resistance is one of the leading causes of failed cancer therapy in the treatment of acute myeloid leukemia. Although the mechanisms of resistance are poorly understood, they may be related to the presence of leukemia stem cells (LSCs). Down-regulation of the miR-203 reportedly contributes to oncogenesis and chemo-resistance in multiple cancers. We found that miR-203 expression was down-regulated in CD34 + AML cells as compared with CD34− cells isolated from patients as well as in LSC-enriched (CD34 + CD38−) cell lines KG-1a or MOLM13. Additionally, re-expression of miR-203 led to decreased cell proliferation, self-renewal, and sphere formation in LSCs. Moreover, miR-203 was found to directly target the 3′un-translated regions of survivin and Bmi-1 mRNAs affecting proliferation and self-renewal in LSCs. In this study, we identified a novel miR-203/survivin/Bmi-1 axis involved in the regulation of biological properties of LSCs. This axis may represent a new therapeutic target for acute myeloid leukemia and a potential prognosis/diagnostic marker for LSCs therapy.

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Most cited references 37

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Evolution of the cancer stem cell model.

Antonija Kreso, John E. Dick (2014)

Genetic analyses have shaped much of our understanding of cancer. However, it is becoming increasingly clear that cancer cells display features of normal tissue organization, where cancer stem cells (CSCs) can drive tumor growth. Although often considered as mutually exclusive models to describe tumor heterogeneity, we propose that the genetic and CSC models of cancer can be harmonized by considering the role of genetic diversity and nongenetic influences in contributing to tumor heterogeneity. We offer an approach to integrating CSCs and cancer genetic data that will guide the field in interpreting past observations and designing future studies. Copyright © 2014 Elsevier Inc. All rights reserved.

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A skin microRNA promotes differentiation by repressing 'stemness'.

Rui Yi, Matthew Poy, Markus Stoffel … (2008)

In stratified epithelial tissues, homeostasis relies on the self-renewing capacity of stem cells located within the innermost basal layer. As basal cells become suprabasal, they lose proliferative potential and embark on a terminal differentiation programme. Here, we show that microRNA-203 is induced in the skin concomitantly with stratification and differentiation. By altering miR-203's spatiotemporal expression in vivo, we show that miR-203 promotes epidermal differentiation by restricting proliferative potential and inducing cell-cycle exit. We identify p63 as one of the conserved targets of miR-203 across vertebrates. Notably, p63 is an essential regulator of stem-cell maintenance in stratified epithelial tissues. We show that miR-203 directly represses the expression of p63: it fails to switch off suprabasally when either Dicer1 or miR-203 is absent and it becomes repressed basally when miR-203 is prematurely expressed. Our findings suggest that miR-203 defines a molecular boundary between proliferative basal progenitors and terminally differentiating suprabasal cells, ensuring proper identity of neighbouring layers.

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Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression.

Maria J Bueno, Ignacio Pérez de Castro, Marta Gómez de Cedrón … (2008)

The mammalian genome contains several hundred microRNAs that regulate gene expression through modulation of target mRNAs. Here, we report a fragile chromosomal region lost in specific hematopoietic malignancies. This 7 Mb region encodes about 12% of all genomic microRNAs, including miR-203. This microRNA is additionally hypermethylated in several hematopoietic tumors, including chronic myelogenous leukemias and some acute lymphoblastic leukemias. A putative miR-203 target, ABL1, is specifically activated in these hematopoietic malignancies in some cases as a BCR-ABL1 fusion protein (Philadelphia chromosome). Re-expression of miR-203 reduces ABL1 and BCR-ABL1 fusion protein levels and inhibits tumor cell proliferation in an ABL1-dependent manner. Thus, miR-203 functions as a tumor suppressor, and re-expression of this microRNA might have therapeutic benefits in specific hematopoietic malignancies.

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Author and article information

Journal

Journal ID (nlm-ta): Sci Rep

Journal ID (iso-abbrev): Sci Rep

Title: Scientific Reports

Publisher: Nature Publishing Group

ISSN (Electronic): 2045-2322

Publication date (Electronic): 05 February 2016

Publication date Collection: 2016

Volume: 6

Electronic Location Identifier: 19995

Affiliations

[1 ]College of life science and technology, Jinan University , Guangzhou, 510632, P.R. China

[2 ]Institute of Biomedicine, Jinan University , Guangzhou, 510632, P.R. China

[3 ]Department of Pathological Physiology, Wan-nan Medical College , Wuhu, 241000, P.R. China

[4 ]College of medicine, Jinan University , Guangzhou, 510632, P.R. China

[5 ]Department of Pathogen Biology and Immunology, Medical College, Guangdong Pharmaceutical University , Guangzhou 510006, China

[6 ]Department of Endoscopy, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China,Collaborative Innovation Center for Cancer Medicine , Guangzhou, 510632, P.R. China

[7 ]Section of Otolaryngology, Department of Surgery, Yale School of Medicine, U.S.A

Author notes

[a ] zhangrong@ 123456sysucc.org.cn

[b ] twang-yf@ 123456163.com

[*]

These authors contributed equally to this work.

Article

Publisher Item ID: srep19995

DOI: 10.1038/srep19995

PMC ID: 4742816

PubMed ID: 26847520

SO-VID: 153a650d-9b9c-416b-9c34-43e5f18f4e02

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miR-203 inhibits proliferation and self-renewal of leukemia stem cells by targeting survivin and Bmi-1

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Most cited references 37

Evolution of the cancer stem cell model.

A skin microRNA promotes differentiation by repressing 'stemness'.

Genetic and epigenetic silencing of microRNA-203 enhances ABL1 and BCR-ABL1 oncogene expression.

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