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Tumor suppressor Fbxw7 antagonizes WNT signaling by targeting β-catenin for degradation in pancreatic cancer

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Tumor Biology

Abstract

Pancreatic cancer is one of the deadliest solid malignancies associated with aberrant Wnt signaling activation. Fbxw7 mutations have been implicated in the development of pancreatic cancer, whereas the exact mechanism of this ubiquitin ligase as a tumor suppressor remains unclear in pancreatic carcinogenesis. Here, we describe that Fbxw7 is downregulated upon pancreatic cancer development. Depletion of Fbxw7 results in tumor suppression in pancreatic cancer cells, while Fbxw7 overexpression inhibits pancreatic cancer cell proliferation and invasion. Considering the negative correlation between Fbxw7 and β-catenin, we find that Fbxw7 antagonizes Wnt signaling through targeting β-catenin for its degradation. Moreover, the inhibitory effect of Fbxw7 on pancreatic cancer cell proliferation is mainly executed by the destruction of the Wnt/β-catenin signaling pathway. We also reveal that c-myc, a widely accepted target of Fbxw7, is also transcriptionally regulated by the Fbxw7/β-catenin axis in pancreatic cancer cells. Collectively, our results demonstrate that Fbxw7 is a novel regulator of Wnt/β-catenin signaling-dependent regulation of pancreatic cancer cell growth and invasion, and inactivation of Fbxw7 in pancreatic cancer tissues might be the reason for the aberrant activation of Wnt signaling.

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Acknowledgments

This project was supported by the International Science and Technology Cooperation Program of China (No. 2014DFA31420) and the National Natural Science Foundation of China (No. 81160311).

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Authors and Affiliations

  1. Department of Biliary-Hepatic SurgeryAffiliated Hospital of Guiyang Medical College, Guiyang, 550001, China

    Jian-xin Jiang, Cheng-yi Sun, She Tian, Chao Yu, Mei-yuan Chen & Hao Zhang

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  1. Jian-xin Jiang
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  2. Cheng-yi Sun
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  3. She Tian
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  4. Chao Yu
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  5. Mei-yuan Chen
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  6. Hao Zhang
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Correspondence to Cheng-yi Sun.

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This study was approved by the Ethics Committee of the Affiliated Hospital of Guiyang Medical College, China. Written informed consent was obtained from each participant.

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Jiang, Jx., Sun, Cy., Tian, S. et al. Tumor suppressor Fbxw7 antagonizes WNT signaling by targeting β-catenin for degradation in pancreatic cancer. Tumor Biol. 37, 13893–13902 (2016). https://doi.org/10.1007/s13277-016-5217-5

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  • DOI: https://doi.org/10.1007/s13277-016-5217-5

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