EVI1 splice variants modulate functional responses in ovarian cancer cells

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• 作者：Punashi Dutta^a ; Tuyen Bui^c ; Kyle A. Bauckman^b ; Khandan Keyomarsi^c ; Gordon B. Mills^d ; Meera Nanjundan^a ; ^b ; ^{mnanjund@usf.edu}
• 关键词：EVI1 ; Ovarian cancer ; TGF¦Â ; Splice variants ; Claudin-1 ; EMT ; Cyclin E1 ; Motility
• 刊名：Molecular Oncology
• 出版年：2013
• 出版时间：June, 2013
• 年：2013
• 卷：7
• 期：3
• 页码：647-668
• 全文大小：6038 K

文摘

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 Del^190-515 variant (equivalent to previously reported) expressed in >90 % of advanced stage serous epithelial ovarian cancers. Although EVI1^Del190-515 lacks ¡«70 % of exon 7, it binds CtBP1 as well as SMAD3, important mediators of TGF¦Â signaling, similar to wild type EVI1. This contrasts with EVI1 1-268 which failed to interact with CtBP1. Interestingly, the EVI1^Del190-515 splice variant preferentially localizes to PML nuclear bodies compared to wild type and EVI1^Del427-515. While wild type EVI1 efficiently repressed TGF¦Â-mediated AP-1 (activator protein-1) and plasminogen activator inhibitor-1 (PAI-1) promoters, EVI1^Del190-515 elicited a slight increase in both promoter activities. Expression of EVI1 and EVI1^Del427-515 (but not EVI1^Del190-515) 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 EVI1^Del190-515) 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.