Abstract |
Advanced cutaneous T-cell lymphoma (CTCL) is resistant to chemotherapy and presents a major area of medical need. In view of the known role of microRNAs ( miRNAs) in the regulation of cellular signalling, we aimed to identify the functionally important miRNA species, which regulate apoptosis in CTCL. Using a recently established model in which apoptosis of CTCL cell lines is induced by Notch-1 inhibition by γ- secretase inhibitors (GSIs), we found that miR-122 was significantly increased in the apoptotic cells. miR-122 up-regulation was not specific for GSI-1 but was also seen during apoptosis induced by chemotherapies including doxorubicin and proteasome blockers ( bortezomib, MG132). miR-122 was not expressed in quiescent T-cells, but was detectable in CTCL: in lesional skin in mycosis fungoides and in Sézary cells purified from peripheral blood. In situ hybridization results showed that miR-122 was expressed in the malignant T-cell infiltrate and increased in the advanced stage mycosis fungoides. Surprisingly, miR-122 overexpression decreased the sensitivity to the chemotherapy-induced apoptosis via a signaling circuit involving the activation of Akt and inhibition of p53. We have also shown that induction of miR-122 occurred via p53 and that p53 post-transcriptionally up-regulated miR-122. miR-122 is thus an amplifier of the antiapoptotic Akt/p53 circuit and it is conceivable that a pharmacological intervention in this pathway may provide basis for novel therapies for CTCL.
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Authors | Valentina Manfè, Edyta Biskup, Anne Rosbjerg, Maria Kamstrup, Anne Guldhammer Skov, Catharina Margrethe Lerche, Britt Thyssing Lauenborg, Niels Odum, Robert Gniadecki |
Journal | PloS one
(PLoS One)
Vol. 7
Issue 1
Pg. e29541
( 2012)
ISSN: 1932-6203 [Electronic] United States |
PMID | 22235305
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antineoplastic Agents
- MIRN122 microRNA, human
- MicroRNAs
- Tumor Suppressor Protein p53
- Proto-Oncogene Proteins c-akt
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Topics |
- Aged
- Aged, 80 and over
- Antineoplastic Agents
(pharmacology, therapeutic use)
- Apoptosis
(drug effects, genetics)
- Cell Line, Tumor
- Female
- Gene Expression Regulation, Neoplastic
(drug effects)
- Humans
- Lymphoma, T-Cell, Cutaneous
(drug therapy, genetics, pathology)
- Male
- MicroRNAs
(genetics, metabolism)
- Middle Aged
- Proto-Oncogene Proteins c-akt
(metabolism)
- Signal Transduction
(drug effects, genetics)
- Skin Neoplasms
(drug therapy, genetics, pathology)
- Tumor Suppressor Protein p53
(metabolism)
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