Evaluation of EVI1 and EVI1s (Delta324) as potential therapeutic targets in ovarian cancer.
OBJECTIVE
The MDS1 and EVI1 complex locus (MECOM) at 3q26 gives rise to several alternatively spliced transcripts implicated in leukemic oncogenesis. Overexpression of EVI1 in ovarian cancer has led to a proposed oncogenic role. Our objective was to evaluate the therapeutic potential of EVI1 and EVI1s (also known as Delta324) in ovarian cancer.


METHODS
Expression of EVI1 mRNA and protein isoforms was evaluated in ovarian cancers, normal ovaries, benign ovarian neoplasms, and fallopian tube fimbria. Effects of EVI1 isoform overexpression and knockdown on proliferation, cisplatin-induced apoptosis, and double stranded DNA breaks were investigated.


RESULTS
EVI1 and EVI1s mRNAs were ubiquitously expressed in ovarian cancers and benign gynecologic tissues examined, with highest expression of both isoforms noted in the cancer samples. The EVI1s to total EVI1 mRNA ratio was uniform among the examined tissues. In contrast, EVI1 protein isoform levels were undetectable in normal ovarian tissues, and highest in serous ovarian cancers. EVI1 protein expression patterns were similar between serous ovarian cancer samples, fallopian tube fimbria, and benign neoplasms. Expression of EVI1 or EVI1s did not increase proliferation in EVI1-null OVCAR8 cells. Total and isoform selective knockdown of EVI1 isoforms in EVI1 expressing ovarian cancer cells had no effect on proliferation, cisplatin-induced apoptosis, or gamma-H2AX levels in ovarian cancer cells.


CONCLUSIONS
Our data do not support a role for EVI1 or EVI1s in ovarian cancer cell proliferation or response to DNA damage. Further research is required before EVI1 can be considered an oncogene or a therapeutic target in ovarian cancer.
Jazaeri
Amir A
AA
W. Norman Thornton Division of Gynecologic Oncology, Department of Obstetrics & Gynecology, University of Virginia Health System, Charlottesville, VA 22908, USA. aj2a@virginia.edu
Ferriss
J Stuart
JS
Bryant
Jennifer L
JL
Dalton
M Susan
MS
Dutta
Anindya
A
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D048708:Cell Growth Processes / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D016503:Drug Delivery Systems; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D020033:Protein Isoforms; D011519:Proto-Oncogenes / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D004268:DNA-Binding Proteins; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D020033:Protein Isoforms; D012333:RNA, Messenger; D014157:Transcription Factors; D002945:Cisplatin