title: Downregulation of Smurf2 ubiquitin ligase in pancreatic cancer cells reversed TGF-β-induced tumor formation.
abstract: Smad ubiquitin regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that regulates transforming growth factor β (TGF-β)/Smad signaling and is implicated in a wide range of cellular responses. However, the exact mechanism whereby Smurf2 controls TGF-β-induced signaling pathways remains unknown. Here, we identified the relationship between the alternate TGF-β signaling pathways: TGF-β/PI3K/Akt/β-catenin and TGF-β/Smad2/3/FoxO1/PUMA and Smurf2. The results showed that TGF-β promoted proliferation, invasion, and migration of human pancreatic carcinoma (PANC-1) cells through the PI3K/Akt/β-catenin pathway. Inhibiting the PI3K/Akt signal transformed the TGF-β-induced cell response from promoting proliferation to Smad2/3/FoxO1/PUMA-mediated apoptosis. The activation of Akt inhibited the phosphorylation/activation of Smad3 and promoted the phosphorylation/inactivation of FoxO1, inhibiting the nuclear translocation of both Smad3 and FoxO1 and inhibiting the expression of PUMA, a key apoptotic mediator. However, downregulation of Smurf2 in PANC-1 cells removed Akt-mediated suppression of Smad3 and FoxO1, allowing TGF-β-induced phosphorylation/activation of Smad2/3, dephosphorylation/activation of FoxO1, nuclear translocation of both factors, and activation of PUMA-mediated apoptosis. Downregulation of Smurf2 also decreased invasion and migration in TGF-β-induced PANC-1 cells. The in vivo experiments also revealed that downregulation of Smurf2 delayed the growth of xenograft tumors originating from PANC-1 cells especially when treated with TGF-β. Taken together, these results indicate that expression of Smurf2 plays a central role in the determination and activation/inhibition of particular cellular pathways and the ultimate fate of cells induced by TGF-β. An increased understanding of the intricacies of the TGF-β signaling pathway may provide a new anti-cancer therapeutic target.
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi Shan Road, Shanghai, 200233, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Wu
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi Shan Road, Shanghai, 200233, China.
authors.forename: Bomin
authors.initials: B
authors.lastname: Guo
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi Shan Road, Shanghai, 200233, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Kang
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi Shan Road, Shanghai, 200233, China.
authors.forename: Xianzhao
authors.initials: X
authors.lastname: Deng
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi Shan Road, Shanghai, 200233, China.
authors.forename: Youben
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Institution of Interventional and Vascular Surgery, Tongji Univerity, No. 301 Middle Yan Chang Rd, Shanghai, 200072, China. zxpkxy@126.com.
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, 600 Yi Shan Road, Shanghai, 200233, China. akxing8258@sina.com.
authors.forename: Kaixing
authors.initials: K
authors.lastname: Ai
keywords: Invasion; Migration; Pancreatic carcinoma; Smad ubiquitin regulatory factor 2; Transforming growth factor β