Role of TGF-? signaling in uterine carcinosarcoma.

ABSTRACT: Uterine carcinosarcomas (UCS) are rare (3-4%) but highly aggressive, accounting for a disproportionately high (16.4%) mortality among uterine malignancies. Transforming growth factor beta (TGF?) is a multifunctional cytokine that regulates important cellular processes including epithelial-mesenchymal transition (EMT). Existence of biphasic elements and a report demonstrating amplification of TGF? at 19q13.1 prompted us to investigate the role of TGF? signaling in UCS.Here we demonstrated the components of TGF? pathway are expressed and functional in UCS. TGF?-I induced significant Smad2/3 phosphorylation, migration and EMT responses in UCS cell lines which could be attenuated by the TGF? receptor I (TGF?R-I) or TGF? receptor I/II (TGF?R-I/II) inhibitor developed by Eli Lilly and company. Importantly, TGF?-I induced proliferation was c-Myc dependent, likely through activation of cell cycle. c-Myc was induced by nuclear translocation of nuclear factor of activated T cells (NFAT-1) in response to TGF?-I. Inhibition of NFAT-1 or TGF?R-I blocked c-Myc induction, cell cycle progression and proliferation in UCS. In corroboration, mRNA levels of c-Myc were elevated in recurrent versus the non-recurrent UCS patient samples. Interestingly, in the absence of exogenous TGF? the TGF?R-I/II inhibitor enhanced proliferation likely through non-Smad pathways. Thus, inhibition of TGF?R-I could be efficacious in treatment of UCS.

SUBMITTER: Dwivedi SK 

PROVIDER: S-EPMC4546494 | biostudies-literature | 2015 Jun

REPOSITORIES: biostudies-literature