Nuclear prothymosin ? suppresses TGF-β-induced epithelial-mesenchymal?transition in lung cancer

Abstract

The multifunctional cytokine transforming growth factor β (TGF-β) regulates a complicated signaling network In cancer progression TGF-β exerts its tumor-suppressive role by inducing cell-cycle arrest and apoptosis at early stages Nevertheless at the late stages of cancer TGF-β promotes tumor progression by enhancing migration and invasion to induce epithelial-mesenchymal transition (EMT) EMT has been shown to be a critical mechanism of tumor cell metastatic dissemination by endowing cells with a more motile invasive potential Prothymosin ? (ProT) is an acidic nuclear protein and an important regulator of cell proliferation transcription chromatin remodeling and immunomodulation We found immunohistochemically that ProT expression was associated with cancer progression At the early stage ProT was overexpressed in the nucleus and during disease progression ProT expression was decreased and its nuclear expression was even lost Therefore we hypothesized that nuclear ProT may play a pivotal role in interrupting TGF-β signaling resulting in inducing EMT We found that TGF-β-induced downregulation of E-cadherin and upregulation of Snail and N-cadherin could be supressed by ProT overexpression in A549 cells Moreover we demonstrated that ProT could antagonize TGF-β signaling through enhancing Smad7 acetylation and stability We further showed that Smad7 disrupted the binding of Smad2 to the promoter of Snail1 a TGF-β-induced EMT-associated regulator leading to downregulating Snail1 expression In addition we found that human lung cancer A549 cells overexpressing PoT exhibited lower metastatic potential than parental A549 cells in NOD/SCID mice In human lung cancer specimens there was an inverse correlation between nuclear ProT and Snail expression In conclusion nuclear ProT expression enhances Smad7 acetylation to antagonize TGF-β signaling which competes the Smad2-binding site on the Snail1 promoter to reduce Snail1 expression and inhibit TGF-β-induced EMT

Date of Award	2015 Aug 14
Original language	English
Supervisor	Chao-Liang Wu (Supervisor)