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Abrogation of glutathione peroxidase-1 drives EMT and chemoresistance in pancreatic cancer by activating ROS-mediated Akt/GSK3β/Snail signaling

Oncogene (2018) | Download Citation

Abstract

The devastating prognosis of pancreatic ductal adenocarcinoma (PDAC) is partially attributed to chemotherapy resistance. Glutathione peroxidase-1 (GPx1) plays various roles in the development and progression of multiple tumors, with the exception of pancreatic cancer. Here, we tentatively explored the role of GPx1 in the malignant biological behavior and gemcitabine (GEM) resistance of PDAC. GPx1 levels were detected using tissue microarrays and were negatively correlated with the overall survival of patients with PDAC. GPx1 silencing induced a mesenchymal transition phenotype and increased GEM resistance in vitro and in vivo. Additionally, the activation of reactive oxygen species (ROS)-mediated Akt/glycogen synthase kinase 3β (GSK3β)/Snail signaling was involved in this process, as determined by RNA sequencing. Moreover, low GPx1 expression correlated with a worse survival rate in patients with PDAC who received GEM adjuvant chemotherapy, whereas this correlation was not detected in patients receiving fluoropyrimidine. Based on our results, GPx1 inhibits the epithelial–mesenchymal transition (EMT) and chemoresistance by regulating the Akt/GSK3β/Snail signaling axis in PDAC. Furthermore, GPx1 may be a potential predictive biomarker in GEM-treated PDAC patients.

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Acknowledgements

We thank Professor Daming Gao (Institutes for Biological Sciences, Chinese Academy of Sciences) and Professor Yi Qin (Cancer Research Institute, Fudan University) for providing critical comments. This study was supported by grants from the National Science Foundation for Distinguished Young Scholars of China (no. 81625016) and the Shanghai Sailing Program (no. 17YF1402500).

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    Affiliations

    1. Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

      • Qingcai Meng
      • , Si Shi
      • , Chen Liang
      • , Dingkong Liang
      • , Jie Hua
      • , Bo Zhang
      • , Jin Xu
      •  & Xianjun Yu
    2. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

      • Qingcai Meng
      • , Si Shi
      • , Chen Liang
      • , Dingkong Liang
      • , Jie Hua
      • , Bo Zhang
      • , Jin Xu
      •  & Xianjun Yu
    3. Shanghai Pancreatic Cancer Institute, Shanghai, 200032, China

      • Qingcai Meng
      • , Si Shi
      • , Chen Liang
      • , Dingkong Liang
      • , Jie Hua
      • , Bo Zhang
      • , Jin Xu
      •  & Xianjun Yu
    4. Pancreatic Cancer Institute, Fudan University, Shanghai, 200032, China

      • Qingcai Meng
      • , Si Shi
      • , Chen Liang
      • , Dingkong Liang
      • , Jie Hua
      • , Bo Zhang
      • , Jin Xu
      •  & Xianjun Yu

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    The authors declare that they have no conflict of interest.

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    Correspondence to Xianjun Yu.

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    https://doi.org/10.1038/s41388-018-0392-z