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Rab11a sustains GSK3β/Wnt/β-catenin signaling to enhance cancer progression in pancreatic cancer

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Tumor Biology

Abstract

The Rab family GTPases regulate many major biological processes during tumor progression such as cell proliferation, cytoskeleton organization, cell movement, and invasion. The present study aims to examine the clinical significance, biological roles, and molecular mechanism of Rab11a in pancreatic cancer progression. We examined expression pattern of Rab11a in 96 cases of pancreatic cancer specimens using immunohistochemistry and found Rab11a overexpression correlated with tumor-node-metastasis (TNM) stage (p = 0.0111). We depleted Rab11a in Bxpc3 cells using small interfering RNA (siRNA) and overexpressed Rab11a in Capan2 cells. Knockdown of Rab11a inhibited cell growth, invasion, and cell cycle progression while its overexpression facilitated cell growth, invasion, and cell cycle progression. In addition, Rab11a overexpression increased gemcitabine resistance and inhibited gemcitabine-induced apoptosis in Capan2 cells while its depletion reduced drug resistance. We investigated the role of Rab11a in the regulation of Wnt/β-catenin signaling and we demonstrated that Rab11a overexpression upregulated GSK3β phosphorylation and nuclear β-catenin accumulation. Rab11a depletion inhibited while its overexpression enhanced β-catenin/T-cell factor (TCF) transcriptional activity with corresponding change of Wnt target genes including cyclin D1, cyclin E, MMP7, and c-myc. Wnt inhibitor (FH535) partly attenuated the effects of Rab11a on cell proliferation and Wnt target genes. In conclusion, the present study demonstrated that Rab11a promotes aggressiveness of pancreatic cancer through GSK3β/Wnt/β-catenin signaling pathway.

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Acknowledgments

This study was supported by China NSFC project (no. 31371177) and Health and Family Planning Commission of Liaoning project Province (LNCCC-D31-2015).We thank Dr. Yang Wang and Dr. Yang Liu for IHC evaluation.

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Authors and Affiliations

  1. Department of Physiology, Jinzhou Medical University, Jinzhou, Liaoning, China

    Li Yu

  2. Key Laboratory of Age-Related Macular Degeneration, The Third Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning, China

    Li Yu & Hua Liu

  3. The Central Hospital of Jinzhou, Liaoning, China

    Xin Li

  4. Department of Ophthalmology, The Third Affiliated Hospital of Jinzhou Medical University, Liaoning, China

    Haibin Li, Huixin Chen & Hua Liu

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  1. Li Yu
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  2. Xin Li
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  3. Haibin Li
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  5. Hua Liu
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Correspondence to Li Yu or Hua Liu.

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Yu, L., Li, X., Li, H. et al. Rab11a sustains GSK3β/Wnt/β-catenin signaling to enhance cancer progression in pancreatic cancer. Tumor Biol. 37, 13821–13829 (2016). https://doi.org/10.1007/s13277-016-5172-1

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  • DOI: https://doi.org/10.1007/s13277-016-5172-1

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