Abstract |
MicroRNAs ( miRNAs) are short noncoding RNAs that play crucial roles in tumorigenesis and tumor progression. Melanoma is the most aggressive skin cancer that is resistant or rapidly develops resistance to a variety of chemotherapeutic agents. The role of miRNAs in melanoma progression and drug resistance has not been well studied. Herein, we demonstrate that miR-200c is down-regulated in melanomas (primary and metastatic) compared with melanocytic nevi. Overexpression of miR-200c in melanoma cells resulted in significantly decreased cell proliferation and migratory capacity as well as drug resistance. miR-200c overexpression resulted in significant down-regulation of BMI-1, ABCG2, ABCG5, and MDR1 expression and in a concomitant increase in E-cadherin levels. Knockdown of BMI-1 showed similar effects as miR-200c overexpression in melanoma cells. In addition, miR-200c overexpression significantly inhibited melanoma xenograft growth and metastasis in vivo, and this correlated with diminished expression of BMI-1 and reduced levels of E-cadherin in these tumors. The effects of miR-200c on melanoma cell proliferation and migratory capacity and on self-renewal were rescued by overexpression of Bmi-1, and the reversal of these phenotypes correlated with a reduction in E-cadherin expression and increased levels of ABCG2, ABCG5, and MDR1. Taken together, these findings demonstrate a key role for miR-200c in melanoma progression and drug resistance. These results suggest that miR-200c may represent a critical target for increasing melanoma sensitivity to clinical therapies.
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Authors | Shujing Liu, Michael T Tetzlaff, Rutao Cui, Xiaowei Xu |
Journal | The American journal of pathology
(Am J Pathol)
Vol. 181
Issue 5
Pg. 1823-35
(Nov 2012)
ISSN: 1525-2191 [Electronic] United States |
PMID | 22982443
(Publication Type: Journal Article, Research Support, N.I.H., Extramural)
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Copyright | Copyright © 2012 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. |
Chemical References |
- BMI1 protein, human
- Cadherins
- MIRN200 microRNA, human
- MicroRNAs
- Neoplasm Proteins
- RNA, Messenger
- Polycomb Repressive Complex 1
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Topics |
- Animals
- Cadherins
(metabolism)
- Cell Line, Tumor
- Cell Movement
(genetics)
- Cell Proliferation
- Disease Progression
- Down-Regulation
(genetics)
- Drug Resistance, Neoplasm
(genetics)
- Gene Expression Regulation, Neoplastic
- Gene Knockdown Techniques
- Humans
- Male
- Melanoma
(genetics, pathology)
- Mice
- Mice, Nude
- MicroRNAs
(genetics, metabolism)
- Neoplasm Metastasis
- Neoplasm Proteins
(genetics, metabolism)
- Polycomb Repressive Complex 1
(genetics, metabolism)
- RNA, Messenger
(genetics, metabolism)
- Skin Neoplasms
(genetics, pathology)
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