cMyc/miR-125b-5p signalling determines sensitivity to bortezomib in preclinical model of cutaneous T-cell lymphomas.
cMyc/miR-125b-5p signalling determines sensitivity to bortezomib in preclinical model of cutaneous T-cell lymphomas.
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DOI：
10.1371/journal.pone.0059390
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发表时间：
2013
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;Willumsgaard A;Skov AG;Palmieri D;Gasparini P;Laganá A;Woetmann A;Ødum N;Croce CM;Gniadecki R
在低级别淋巴瘤中，成功/有效的癌症治疗常常受到细胞对抗肿瘤药物的耐药性的阻碍。造成这一现象的关键机制鲜为人知。克服肿瘤细胞对蛋白酶体抑制剂等抗癌药物的耐药性，可以提高其临床疗效。利用皮肤T细胞淋巴瘤(CTCL)作为化疗耐药外周淋巴系统恶性肿瘤的模型，我们证明了对蛋白酶体抑制的抵抗涉及癌基因cMyc和miR-125b-5p之间的信号转导。Bortezomib抑制cMyc，同时诱导miR-125b-5p，通过下调MAD4发挥细胞保护作用。CMyc的过表达抑制了miR-125b-5p的转录，并使淋巴瘤细胞对硼替佐米增敏。MiR-125b-5p的中心作用在T细胞淋巴瘤小鼠模型中得到进一步证实，在该模型中，高表达miR-125b-5p的人CTCL细胞异种移植可促进肿瘤生长并缩短中位生存期。我们的发现描述了一种新的机制，通过miR-125b-5p不仅调节体内肿瘤的生长，而且通过调节MAD4增加细胞对蛋白酶体抑制剂的抵抗。
Successful/effective cancer therapy in low grade lymphoma is often hampered by cell resistance to anti-neoplastic agents. The crucial mechanisms responsible for this phenomenon are poorly understood. Overcoming resistance of tumor cells to anticancer agents, such as proteasome inhibitors, could improve their clinical efficacy. Using cutaneous T-cell lymphoma (CTCL) as a model of the chemotherapy-resistant peripheral lymphoid malignancy, we demonstrated that resistance to proteasome inhibition involved a signaling between the oncogene cMyc and miR-125b-5p. Bortezomib repressed cMyc and simultaneously induced miR-125b-5p that exerted a cytoprotective effect through the downmodulation of MAD4. Overexpression of cMyc repressed miR-125b-5p transcription and sensitized lymphoma cells to bortezomib. The central role of miR-125b-5p was further confirmed in a mouse model of T-cell lymphoma, where xenotransplantation of human CTCL cells overexpressing miR-125b-5p resulted in enhanced tumor growth and a shorter median survival. Our findings describe a novel mechanism through which miR-125b-5p not only regulates tumor growth in vivo, but also increases cellular resistance to proteasome inhibitors via modulation of MAD4.
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影响因子：
3
作者：
KALTOFT, K;BISBALLE, S;STERRY, W
通讯作者：
STERRY, W
影响因子：
7.3
作者：
Gibcus, Johan H.;Kroesen, Bart-Jan;van den Berg, Anke
通讯作者：
van den Berg, Anke
影响因子：
2.6
作者：
Guo, Xiao-Ling;Pan, Ling;Ohno, Ruzo
通讯作者：
Ohno, Ruzo
DOI：
10.1084/jem.20080285
发表时间：
2008-10-27
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Bousquet M;Quelen C;Rosati R;Mansat-De Mas V;La Starza R;Bastard C;Lippert E;Talmant P;Lafage-Pochitaloff M;Leroux D;Gervais C;Viguié F;Lai JL;Terre C;Beverlo B;Sambani C;Hagemeijer A;Marynen P;Delsol G;Dastugue N;Mecucci C;Brousset P
通讯作者：
Brousset P
影响因子：
4.7
作者：
Chim, C. S.;Wong, K. Y.;Liang, R.
通讯作者：
Liang, R.