EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer.
EMT transcription factors snail and slug directly contribute to cisplatin resistance in ovarian cancer.
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DOI：
10.1186/1471-2407-12-91
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发表时间：
2012-03-19
期刊：
影响因子：
3.8
通讯作者：
Feilotter H
中科院分区：
文献类型：
--
作者：
Haslehurst AM;Koti M;Dharsee M;Nuin P;Evans K;Geraci J;Childs T;Chen J;Li J;Weberpals J;Davey S;Squire J;Park PC;Feilotter H
上皮细胞向间充质细胞转化（EMT）是上皮细胞转分化为间充质细胞的一个分子过程。EMT在胚胎发生中的作用已经得到了很好的表征，越来越多的证据表明，这种转变的元素在其他过程中可能很重要，包括各种不同癌症的转移和耐药性。采用Agilent 4 × 44 K全基因组芯片和选择反应监测质谱技术研究A2780顺铂敏感和耐药细胞株的mRNA和蛋白表达。使用博伊登室测定法评估入侵和迁移。使用靶向siRNA进行蜗牛和蛞蝓的基因敲低。使用来自AffytechnologyGeneChip人类基因组U133加2.0阵列的数据，在一组原发性卵巢肿瘤中评估EMT途径的临床相关性。在耐药细胞中鉴定了EMT的形态学和表型特征。随后的基因表达谱显示EMT相关转录因子包括snail、slug、twist 2和zeb 2的上调。蛋白质组学分析显示Snail和Slug以及间充质标志物波形蛋白上调，上皮标志物E-钙粘蛋白下调。通过减少snail和slug的表达，间充质表型在很大程度上被逆转，细胞对顺铂重新敏感。最后，原发性肿瘤的基因表达数据反映了这样的发现，即相对于敏感肿瘤，耐药肿瘤中的EMT样途径被激活，这表明这种转变的参与可能不仅限于体外药物作用。这项工作强烈表明，与EMT相关的基因可能在卵巢癌顺铂耐药中发挥重要作用，因此可能导致开发药物反应的预测生物标志物或克服耐药性的新治疗策略。
The epithelial to mesenchymal transition (EMT) is a molecular process through which an epithelial cell undergoes transdifferentiation into a mesenchymal phenotype. The role of EMT in embryogenesis is well-characterized and increasing evidence suggests that elements of the transition may be important in other processes, including metastasis and drug resistance in various different cancers. Agilent 4 × 44 K whole human genome arrays and selected reaction monitoring mass spectrometry were used to investigate mRNA and protein expression in A2780 cisplatin sensitive and resistant cell lines. Invasion and migration were assessed using Boyden chamber assays. Gene knockdown of snail and slug was done using targeted siRNA. Clinical relevance of the EMT pathway was assessed in a cohort of primary ovarian tumours using data from Affymetrix GeneChip Human Genome U133 plus 2.0 arrays. Morphological and phenotypic hallmarks of EMT were identified in the chemoresistant cells. Subsequent gene expression profiling revealed upregulation of EMT-related transcription factors including snail, slug, twist2 and zeb2. Proteomic analysis demonstrated up regulation of Snail and Slug as well as the mesenchymal marker Vimentin, and down regulation of E-cadherin, an epithelial marker. By reducing expression of snail and slug, the mesenchymal phenotype was largely reversed and cells were resensitized to cisplatin. Finally, gene expression data from primary tumours mirrored the finding that an EMT-like pathway is activated in resistant tumours relative to sensitive tumours, suggesting that the involvement of this transition may not be limited to in vitro drug effects. This work strongly suggests that genes associated with EMT may play a significant role in cisplatin resistance in ovarian cancer, therefore potentially leading to the development of predictive biomarkers of drug response or novel therapeutic strategies for overcoming drug resistance.
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DOI：
10.1111/igc.0b013e3181c10513
发表时间：
2009-12-01
影响因子：
4.8
作者：
Marsh, Sharon
通讯作者：
Marsh, Sharon
影响因子：
3
作者：
Cheng, Timothy C.;Manorek, Gerald;Howell, Stephen B.
通讯作者：
Howell, Stephen B.
影响因子：
4.7
作者：
Helleman, Jozien;Smid, Marcel;Berns, Els M. J. J.
通讯作者：
Berns, Els M. J. J.
影响因子：
5.2
作者：
Kurrey, Nawneet K.;Jalgaonkar, Swati P.;Bapat, Sharmila A.
通讯作者：
Bapat, Sharmila A.
影响因子：
15.8
作者：
Köbel M;Kalloger SE;Boyd N;McKinney S;Mehl E;Palmer C;Leung S;Bowen NJ;Ionescu DN;Rajput A;Prentice LM;Miller D;Santos J;Swenerton K;Gilks CB;Huntsman D
通讯作者：
Huntsman D