EVI1 splice variants modulate functional responses in ovarian cancer cells.
EVI1 splice variants modulate functional responses in ovarian cancer cells.
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DOI：
10.1016/j.molonc.2013.02.008
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发表时间：
2013-06
影响因子：
6.6
通讯作者：
Nanjundan, Meera
中科院分区：
文献类型：
--
作者：
Dutta, Punashi;Bui, Tuyen;Bauckman, Kyle A.;Keyomarsi, Khandan;Mills, Gordon B.;Nanjundan, Meera
在许多癌症谱系中发现的3q26.2扩增是卵巢癌中常见的早期事件。我们以前定义了3q26.2到EVI1(生态型病毒整合位点-1)和MDS1(骨髓增生异常综合征1)(又名Mecom)的最频繁的拷贝数增加区域，这一观察结果最近被癌症基因组图谱(TCGA)证实。Mecom在DNA、RNA和蛋白质水平上增加，可能有助于患者的预后。在此，我们报告了EVI1的异常剪接，产生了多种变异，包括Del190-515变异(相当于先前报道的)，在90%的晚期浆液性卵巢上皮癌中表达。虽然EVI1Del190-515缺少70%的∼外显子7，但它结合了CtBP1和Smad3这两个重要的转化生长因子β信号转导因子，类似于野生型EVI1。这与未能与CtBP1相互作用的EVI11-268形成了鲜明对比。有趣的是，与野生型和EVI1Del427-515相比，EVI1Del190-515剪接变异体优先定位于PML核体。野生型EVI1能有效抑制转化生长因子β介导的AP-1和纤溶酶原激活物抑制物-1启动子的活性，而EVI1Del190-515对这两种启动子的活性均有轻微的促进作用。EVI1和EVI1Del427-515(而不是EVI1Del190-515)在OVCAR8卵巢癌细胞中的表达增加了细胞周期蛋白E1LMW的表达和细胞周期的进展。此外，敲除特定的EVI1剪接变异体(MDS1/EVI1和EVI1Del190-515)显著增加了卵巢癌细胞和MDA-MB-231乳腺癌细胞中claudin-1mRNA和蛋白的表达。Claudin-1的变化与特定的上皮-间充质转化标志物的变化有关，同时伴随着迁移潜力的降低。总的来说，EVI1在卵巢癌中经常以特定形式发生异常剪接，引起功能改变，这可能有助于卵巢癌的病理生理。
Amplification of 3q26.2, found in many cancer lineages, is a frequent and early event in ovarian cancer. We previously defined the most frequent region of copy number increase at 3q26.2 to EVI1 (ecotropic viral integration site-1) and MDS1 (myelodysplastic syndrome 1) (aka MECOM), an observation recently confirmed by the cancer genome atlas (TCGA). MECOM is increased at the DNA, RNA, and protein level and likely contributes to patient outcome. Herein, we report that EVI1 is aberrantly spliced, generating multiple variants including a Del190–515 variant (equivalent to previously reported) expressed in >90% of advanced stage serous epithelial ovarian cancers. Although EVI1Del190–515 lacks ∼70% of exon 7, it binds CtBP1 as well as SMAD3, important mediators of TGFβ signaling, similar to wild type EVI1. This contrasts with EVI1 1–268 which failed to interact with CtBP1. Interestingly, the EVI1Del190–515 splice variant preferentially localizes to PML nuclear bodies compared to wild type and EVI1Del427–515. While wild type EVI1 efficiently repressed TGFβ-mediated AP-1 (activator protein-1) and plasminogen activator inhibitor-1 (PAI-1) promoters, EVI1Del190–515 elicited a slight increase in both promoter activities. Expression of EVI1 and EVI1Del427–515 (but not EVI1Del190–515) in OVCAR8 ovarian cancer cells increased cyclin E1 LMW expression and cell cycle progression. Furthermore, knockdown of specific EVI1 splice variants (both MDS1/EVI1 and EVI1Del190–515) markedly increased claudin-1 mRNA and protein expression in HEY ovarian and MDA-MB-231 breast cancer cells. Changes in claudin-1 were associated with alterations in specific epithelial–mesenchymal transition markers concurrent with reduced migratory potential. Collectively, EVI1 is frequently aberrantly spliced in ovarian cancer with specific forms eliciting altered functions which could potentially contribute to ovarian cancer pathophysiology.
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影响因子：
64.8
作者：
通讯作者：
--
影响因子：
8
作者：
Kilbey, A;Bartholomew, C
通讯作者：
Bartholomew, C
DOI：
10.1073/pnas.1119229109
发表时间：
2012-02-07
影响因子：
11.1
作者：
Bard-Chapeau, Emilie A.;Jeyakani, Justin;Copeland, Neal G.
通讯作者：
Copeland, Neal G.
影响因子：
4
作者：
Ikenouchi, J;Matsuda, M;Tsukita, S
通讯作者：
Tsukita, S
影响因子：
4.8
作者：
Chakraborty, S;Senyuk, V;Nucifora, G
通讯作者：
Nucifora, G