ERM/ETV5 up-regulation plays a role during myometrial infiltration through matrix metalloproteinase-2 activation in endometrial cancer.
We have described recently the Ets family transcription factor, ERM/ETV5, specifically up-regulated in endometrioid endometrial carcinoma (EEC) and associated with myometrial infiltration. Ets family members have been correlated to tumor progression by up-regulating the expression of matrix-degrading proteases. In the present study, we investigated the possibility that in EEC, ERM/ETV5 may act by inducing the expression of genes involved in extracellular matrix remodeling. Unraveling the molecular events associated with the initiation of tumor invasion would represent an obvious improvement for EEC patients. The overexpression of ERM/ETV5 induced scattering in the endometrial cancer cell line Hec-1A, correlating to increased matrix metalloproteinase-2 (MMP-2) gelatinase activity. Both chromatin immunoprecipitation and reversion experiments with RNA interference and specific MMP-2 inhibitor showed a functional link between ERM/ETV5 overexpression and MMP-2 activation. The increased MMP-2 activity associated with overexpressed ERM/ETV5 in a mouse model conferred invasive capacity to endometrial tumors. Orthotopically implanted overexpressing ERM/ETV5 tumors presented a more aggressive and infiltrative pattern of myometrial invasion. Finally, the specific localization of ERM/ETV5 and MMP-2 at the invasive front of myometrial infiltrating human endometrial carcinomas further reinforced the hypothesis of a role for ERM/ETV5 in the early steps of endometrial dissemination. Taken together, these results lead us to propose that in EEC, ERM/ETV5 acts through MMP-2 gelatinolytic activity to confer invasive capabilities, associated with an initial switch to myometrial infiltration. They also postulate ERM/ETV5 as a valuable marker for patient stratification and a transcription pathway that should be evaluated for therapies specifically targeting the initial steps of EEC dissemination.
Monge
Marta
M
Research Institute Vall d'Hebron University Hospital, Department of Gynecological Oncology, Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119-129, 08035 Barcelona, Spain.
Colas
Eva
E
Doll
Andreas
A
Gonzalez
Marta
M
Gil-Moreno
Antonio
A
Planaguma
Jesus
J
Quiles
Maite
M
Arbos
Maria Antonia
MA
Garcia
Angel
A
Castellvi
Josep
J
Llaurado
Marta
M
Rigau
Marina
M
Alazzouzi
Hafid
H
Xercavins
Jordi
J
Alameda
Francesc
F
Reventos
Jaume
J
Abal
Miguel
M
D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis*; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D004789:Enzyme Activation; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D051379:Mice; D008969:Molecular Sequence Data; D009215:Myometrium / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D014157:Transcription Factors / Q000096:biosynthesis*
D004268:DNA-Binding Proteins; C086680:ETV5 protein, human; D014157:Transcription Factors; D020778:Matrix Metalloproteinase 2