Transcriptome and proteome analysis of tyrosine kinase inhibitor treated canine mast cell tumour cells identifies potentially kit signaling-dependent genes.
Transcriptome and proteome analysis of tyrosine kinase inhibitor treated canine mast cell tumour cells identifies potentially kit signaling-dependent genes.
复制标题
DOI：
10.1186/1746-6148-8-96
复制
发表时间：
2012-06-29
影响因子：
2.6
通讯作者：
Gruber AD
中科院分区：
文献类型：
--
作者：
Klopfleisch R;Meyer A;Schlieben P;Bondzio A;Weise C;Lenze D;Hummel M;Einspanier R;Gruber AD
犬肥大细胞肿瘤增殖在很大程度上取决于酪氨酸激酶受体KIT的活性。KIT酪氨酸激酶的抑制剂最近已被引入并成功地用作这种肿瘤类型的治疗剂。然而，对该信号通路的下游靶基因以及抑制后的分子变化知之甚少。用酪氨酸激酶抑制剂马赛替尼处理长达72小时的犬肥大细胞肿瘤细胞系C2的转录组分析鉴定了约3500个基因或犬基因组的16%的表达水平的显著变化。这些基因中约40%的mRNA表达水平增加，包括与B-和T-细胞受体、趋化因子受体、类固醇激素受体和EPO-、RAS和MAP激酶信号传导的促增殖途径相关的基因。处理72小时的C2细胞的蛋白质组分析鉴定了24种表达水平改变的蛋白质，其中大部分涉及基因转录，例如EIA 3、EIA 4、TARDBP，蛋白质折叠，例如HSP 90、UCHL 3、PDIA 3和氧化应激保护，GSTT 3、SELENBP 1。用马赛替尼处理的肿瘤性犬肥大细胞的转录组和蛋白质组分析证实了KIT在这些细胞中的强烈的重要和复杂的作用。大约16%的犬基因组，因此大多数的活性基因显着转录调控。这些变化中的大多数与经处理细胞的增殖和代谢降低相关。有趣的是，几种促增殖途径被上调，这可能代表马赛替尼处理的细胞试图激活替代的促增殖途径。这些途径可能包含与马赛替尼联合治疗的假设靶点，以进一步改善其治疗效果。
Canine mast cell tumour proliferation depends to a large extent on the activity of KIT, a tyrosine kinase receptor. Inhibitors of the KIT tyrosine kinase have recently been introduced and successfully applied as a therapeutic agent for this tumour type. However, little is known on the downstream target genes of this signaling pathway and molecular changes after inhibition. Transcriptome analysis of the canine mast cell tumour cell line C2 treated for up to 72 hours with the tyrosine kinase inhibitor masitinib identified significant changes in the expression levels of approximately 3500 genes or 16% of the canine genome. Approximately 40% of these genes had increased mRNA expression levels including genes associated with the pro-proliferative pathways of B- and T-cell receptors, chemokine receptors, steroid hormone receptors and EPO-, RAS and MAP kinase signaling. Proteome analysis of C2 cells treated for 72 hours identified 24 proteins with changed expression levels, most of which being involved in gene transcription, e.g. EIA3, EIA4, TARDBP, protein folding, e.g. HSP90, UCHL3, PDIA3 and protection from oxidative stress, GSTT3, SELENBP1. Transcriptome and proteome analysis of neoplastic canine mast cells treated with masitinib confirmed the strong important and complex role of KIT in these cells. Approximately 16% of the total canine genome and thus the majority of the active genes were significantly transcriptionally regulated. Most of these changes were associated with reduced proliferation and metabolism of treated cells. Interestingly, several pro-proliferative pathways were up-regulated, which may represent attempts of masitinib treated cells to activate alternative pro-proliferative pathways. These pathways may contain hypothetical targets for a combination therapy with masitinib to further improve its therapeutic effect.
登录
查看更多内容
影响因子：
3.7
作者：
Humbert M;Castéran N;Letard S;Hanssens K;Iovanna J;Finetti P;Bertucci F;Bader T;Mansfield CD;Moussy A;Hermine O;Dubreuil P
通讯作者：
Dubreuil P
影响因子：
20.1
作者：
Cardin, Sophie;Libby, Eric;Nattel, Stanley
通讯作者：
Nattel, Stanley
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
0.8
作者：
London, CA;Kisseberth, WC;Helfand, SC
通讯作者：
Helfand, SC
影响因子：
1
作者：
Hahn, Kevin A.;Legendre, Alfred M.;Hermine, Olivier
通讯作者：
Hermine, Olivier