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Downregulation of Smurf2 ubiquitin ligase in pancreatic cancer cells reversed TGF-β-induced tumor formation

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Tumor Biology

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.

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Authors and Affiliations

  1. Department of General Surgery, Shanghai Jiao Tong University Affiliated Sixth People’s Hospital, 600 Yi Shan Road, Shanghai, 200233, China

    Bo Wu, Bomin Guo, Jie Kang, Xianzhao Deng, Youben Fan & Kaixing Ai

  2. Institution of Interventional and Vascular Surgery, Tongji Univerity, No. 301 Middle Yan Chang Rd, Shanghai, 200072, China

    Xiaoping Zhang

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  1. Bo Wu
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  2. Bomin Guo
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  3. Jie Kang
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  4. Xianzhao Deng
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  5. Youben Fan
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  6. Xiaoping Zhang
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  7. Kaixing Ai
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Correspondence to Xiaoping Zhang or Kaixing Ai.

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Bo Wu and Bo-Min Guo have contributed equally to this work.

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Wu, B., Guo, B., Kang, J. et al. Downregulation of Smurf2 ubiquitin ligase in pancreatic cancer cells reversed TGF-β-induced tumor formation. Tumor Biol. 37, 16077–16091 (2016). https://doi.org/10.1007/s13277-016-5432-0

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  • DOI: https://doi.org/10.1007/s13277-016-5432-0

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