BAMBI is overexpressed in ovarian cancer and co-translocates with Smads into the nucleus upon TGF-beta treatment.
OBJECTIVE
Transforming growth factor beta (TGF-beta) signaling via Smads plays a central role in carcinogenesis. Bmp and activin membrane-bound inhibitor (BAMBI) was initially described as a pseudoreceptor antagonizing TGF-beta receptor activation, thus impairing signaling. Here we wanted to estimate the role of BAMBI in ovarian cancer.


METHODS
The function of BAMBI was studied using a cell line model and intracellular localization experiments. The impact of BAMBI expression on patient outcome was estimated by real-time PCR and immunohistochemistry.


RESULTS
We demonstrate for the first time a nuclear co-translocation of BAMBI with Smad2/3 upon TGF-beta treatment. Moreover, overexpression of BAMBI in an in vitro model led to significantly increased proliferation (doubling time -37.0%, P=0.010), migration (+581.2%, P=0.004) and resistance to TGF-beta-mediated apoptosis (decrease of apoptosis from 30% in the control cells to 7% in the BAMBI-overexpressing cells). Although-prima facie-this fits to the thesis of BAMBI as a pseudoreceptor, it may also be explained by modulation of TGF-beta signaling in the nucleus, leading to the observed pro-oncogenic properties. The tumor promoting impact of BAMBI mRNA overexpression in vitro could not be confirmed in primary tumor samples, and while nearly all tumor samples showed up-regulation of BAMBI (37.3% 1+, 39.2% 2+, and 16.7% 3+, respectively) compared to undetectable BAMBI in healthy pre- and post-menopausal ovarian epithelia, no impact of BAMBI expression on recurrence free and overall survival could be observed.


CONCLUSIONS
These findings provide new insights into the Smad-mediated pathway by inferring that BAMBI is a novel modulator of TGF-beta signaling.
Pils
Dietmar
D
Department of Internal Medicine I, Division of Oncology, Medical University of Vienna, Austria. dietmar.pils@univie.ac.at
Wittinger
Michael
M
Petz
Michaela
M
Gugerell
Alfred
A
Gregor
Wolfgang
W
Alfanz
Angela
A
Horvat
Reinhard
R
Braicu
Elena-Ioana
EI
Sehouli
Jalid
J
Zeillinger
Robert
R
Mikulits
Wolfgang
W
Krainer
Michael
M
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051900:Smad3 Protein / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation
C485671:BAMBI protein, human; D008565:Membrane Proteins; D012333:RNA, Messenger; C497782:SMAD2 protein, human; C497790:SMAD3 protein, human; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta