miR-122 regulates p53/Akt signalling and the chemotherapy-induced apoptosis in cutaneous T-cell lymphoma.
miR-122 regulates p53/Akt signalling and the chemotherapy-induced apoptosis in cutaneous T-cell lymphoma.
复制标题
DOI：
10.1371/journal.pone.0029541
复制
发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Gniadecki R
中科院分区：
文献类型：
--
作者：
Manfè V;Biskup E;Rosbjerg A;Kamstrup M;Skov AG;Lerche CM;Lauenborg BT;Odum N;Gniadecki R
晚期皮肤 T 细胞淋巴瘤 (CTCL) 对化疗具有耐药性，是医疗需求的主要领域。鉴于 microRNA (miRNA) 在细胞信号传导调节中的已知作用，我们旨在鉴定功能上重要的 miRNA 种类，它们调节 CTCL 中的细胞凋亡。使用最近建立的模型，通过γ-分泌酶抑制剂（GSI）抑制Notch-1诱导CTCL细胞系凋亡，我们发现凋亡细胞中miR-122显着增加。 miR-122 上调并非 GSI-1 特异的，但在阿霉素和蛋白酶体阻断剂（硼替佐米、MG132）等化疗诱导的细胞凋亡过程中也可见到。 miR-122 在静止 T 细胞中不表达，但在 CTCL 中可检测到：在蕈样肉芽肿的病变皮肤中和从外周血纯化的 Sézary 细胞中。原位杂交结果显示，miR-122在恶性T细胞浸润中表达，并在晚期蕈样肉芽肿中表达增加。令人惊讶的是，miR-122 过表达通过涉及 Akt 激活和 p53 抑制的信号通路降低了对化疗诱导的细胞凋亡的敏感性。我们还表明，miR-122 的诱导是通过 p53 发生的，并且 p53 转录后上调 miR-122。因此，miR-122 是抗凋亡 Akt/p53 回路的放大器，可以想象，对该途径的药理学干预可能为 CTCL 的新疗法提供基础。
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.
登录
查看更多内容
影响因子：
3
作者：
KALTOFT, K;BISBALLE, S;STERRY, W
通讯作者：
STERRY, W
影响因子：
4.8
作者：
Jorgensen, Stine;Baker, Adam;Nielsen, Boye Schnack
通讯作者：
Nielsen, Boye Schnack
影响因子：
11.5
作者：
Marchi, Enrica;Paoluzzi, Luca;O'Connor, Owen A.
通讯作者：
O'Connor, Owen A.
影响因子：
8
作者：
Kimura, SH;Ikawa, M;Nojima, H
通讯作者：
Nojima, H
影响因子：
64.5
作者：
ELLISEN, LW;BIRD, J;SKLAR, J
通讯作者：
SKLAR, J