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.
Highlights
Mycosis fungoides (MF) and Sezary syndrome (SS) are the commonest cutaneous T-cell lymphoma (CTCL) [1]
Results miR-122 is expressed in CTCL and inhibits apoptosis induced by chemotherapy
In order to identify the miRNA species involved in the regulation of apoptosis in CTCL, we investigated the influence of GSIs on miRNA expression pattern in CTCL cell lines
Summary
Mycosis fungoides (MF) and Sezary syndrome (SS) are the commonest cutaneous T-cell lymphoma (CTCL) [1]. SS is a lymphoma-leukaemia syndrome characterized by erythroderma and the presence of a malignant T-cell clone in the peripheral blood and the skin. Advanced cutaneous T-cell lymphoma is an incurable disease and represents an area of a high medical need. Classic anthracycline- or nucleoside analog-based regimens provide only short-lived responses and relapses are invariably observed within a year [2,3]. It has been hypothesized that relapses are caused by a subpopulation of long-lived, mitotically quiescent malignant cells that survive even intensive chemotherapy regimes [4]. Current research efforts are concentrated on a better understanding of chemotherapy resistance in CTCL and on identification of new pharmacological targets [3,5]
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