PMID- 23517670
OWN - NLM
STAT- MEDLINE
DCOM- 20131223
LR  - 20211021
IS  - 1878-0261 (Electronic)
IS  - 1574-7891 (Print)
IS  - 1574-7891 (Linking)
VI  - 7
IP  - 3
DP  - 2013 Jun
TI  - EVI1 splice variants modulate functional responses in ovarian cancer cells.
PG  - 647-68
LID - S1574-7891(13)00032-X [pii]
LID - 10.1016/j.molonc.2013.02.008 [doi]
AB  - 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  approximately 70% of exon 7, it 
      binds CtBP1 as well as SMAD3, important mediators of TGFbeta 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 TGFbeta-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.
CI  - Copyright (c) 2013 Federation of European Biochemical Societies. Published by 
      Elsevier B.V. All rights reserved.
FAU - Dutta, Punashi
AU  - Dutta P
AD  - Department of Cell Biology, Microbiology, and Molecular Biology, University of 
      South Florida, Tampa, FL 33620, USA.
FAU - Bui, Tuyen
AU  - Bui T
FAU - Bauckman, Kyle A
AU  - Bauckman KA
FAU - Keyomarsi, Khandan
AU  - Keyomarsi K
FAU - Mills, Gordon B
AU  - Mills GB
FAU - Nanjundan, Meera
AU  - Nanjundan M
LA  - eng
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - R01 123219/PHS HHS/United States
GR  - R01 CA123219/CA/NCI NIH HHS/United States
GR  - P50 CA098258/CA/NCI NIH HHS/United States
GR  - P50 CA083639/CA/NCI NIH HHS/United States
GR  - R01 CA087548/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130305
PL  - United States
TA  - Mol Oncol
JT  - Molecular oncology
JID - 101308230
RN  - 0 (CCNE1 protein, human)
RN  - 0 (Claudin-1)
RN  - 0 (Cyclin E)
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (MDS1 and EVI1 Complex Locus Protein)
RN  - 0 (MECOM protein, human)
RN  - 0 (Oncogene Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (Transcription Factors)
RN  - 0 (Transforming Growth Factor beta)
SB  - IM
MH  - Carcinoma, Ovarian Epithelial
MH  - Cell Cycle
MH  - Cell Line, Tumor
MH  - Claudin-1/genetics
MH  - Cyclin E/metabolism
MH  - DNA-Binding Proteins/analysis/*genetics/metabolism
MH  - Epithelial-Mesenchymal Transition
MH  - Female
MH  - Gene Deletion
MH  - Gene Expression Regulation, Neoplastic
MH  - Humans
MH  - MDS1 and EVI1 Complex Locus Protein
MH  - Neoplasms, Glandular and Epithelial/*genetics/metabolism/*pathology
MH  - Oncogene Proteins/metabolism
MH  - Ovarian Neoplasms/*genetics/metabolism/*pathology
MH  - Ovary/metabolism/*pathology
MH  - Protein Isoforms/analysis/genetics/metabolism
MH  - Proto-Oncogenes/*genetics
MH  - Transcription Factors/analysis/*genetics/metabolism
MH  - Transcriptional Activation
MH  - Transforming Growth Factor beta/metabolism
PMC - PMC3805042
MID - NIHMS451536
EDAT- 2013/03/23 06:00
MHDA- 2013/12/24 06:00
PMCR- 2013/06/01
CRDT- 2013/03/23 06:00
PHST- 2012/12/09 00:00 [received]
PHST- 2013/01/18 00:00 [revised]
PHST- 2013/02/12 00:00 [accepted]
PHST- 2013/03/23 06:00 [entrez]
PHST- 2013/03/23 06:00 [pubmed]
PHST- 2013/12/24 06:00 [medline]
PHST- 2013/06/01 00:00 [pmc-release]
AID - S1574-7891(13)00032-X [pii]
AID - MOL2201373647 [pii]
AID - 10.1016/j.molonc.2013.02.008 [doi]
PST - ppublish
SO  - Mol Oncol. 2013 Jun;7(3):647-68. doi: 10.1016/j.molonc.2013.02.008. Epub 2013 Mar 
      5.