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Original article
Localisation of PGK1 determines metabolic phenotype to balance metastasis and proliferation in patients with SMAD4-negative pancreatic cancer
  1. Chen Liang1,2,3,4,
  2. Si Shi1,2,3,4,
  3. Yi Qin1,2,3,4,
  4. Qingcai Meng1,2,3,4,
  5. Jie Hua1,2,3,4,
  6. Qiangshen Hu1,2,3,4,
  7. Shunrong Ji1,2,3,4,
  8. Bo Zhang1,2,3,4,
  9. Jin Xu1,2,3,4,
  10. Xian-Jun Yu1,2,3,4
  1. 1 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
  2. 2 Department of Oncology, Shanghai Medical College Fudan University, Shanghai, China
  3. 3 Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
  4. 4 Pancreatic Cancer Institute, Fudan University, Shanghai, China
  1. Correspondence to Professor Xian-Jun Yu, Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; yuxianjun88{at}hotmail.com

Abstract

Objective Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive type of GI tumour, and it possesses deregulated cellular energetics. Although recent advances in PDAC biology have led to the discovery of recurrent genetic mutations in Kras, TP53 and SMAD4, which are related to this disease, clinical application of the molecular phenotype of PDAC remains challenging.

Design We combined molecular imaging technology (positron emission tomography/CT) and immunohistochemistry to evaluate the correlation between the maximum standardised uptake value and SMAD4 expression and examined the effect of SMAD4 on glycolysis through in vitro and in vivo experiments. Furthermore, we identified the effect of SMAD4 on metabolic reprogramming by metabolomics and glucose metabolism gene expression analyses. Dual luciferase reporter assays and chromatin immunoprecipitation were performed to identify whether SMAD4 functioned as a transcription factor for phosphoglycerate kinase 1 (PGK1) in PDAC cells. Proliferative and metastatic assays were performed to examine the effect of PGK1 on the malignant behaviour of PDAC.

Results We provide compelling evidence that the glycolytic enzyme PGK1 is repressed by transforming growth factor-β/SMAD4. Loss of SMAD4 induces PGK1 upregulation in PDAC, which enhances glycolysis and aggressive tumour behaviour. Notably, in SMAD4-negative PDAC, nuclear PGK1 preferentially drives cell metastasis via mitochondrial oxidative phosphorylation induction, whereas cytoplasmic PGK1 preferentially supports proliferation by functioning as a glycolytic enzyme. The PDAC progression pattern and distinct PGK1 localisation combine to predict overall survival and disease-free survival.

Conclusion PGK1 is a decisive oncogene in patients with SMAD4-negative PDAC and can be a target for the development of a therapeutic strategy for SMAD4-negative PDAC.

  • pancreatic cancer
  • SMAD4
  • PGK1
  • metabolic phenotype
  • metastasis
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Footnotes

  • CL, SS and YQ contributed equally.

  • Correction notice This article has been corrected since it published Online First. Figure 3 has been amended.

  • Contributors CL, SS and X-JY conceived and designed the strategies. CL and YQ performed the in vitro experiments with cell lines, analysed the data and wrote the paper. XJ-Y supervised the project. BZ, SJ and QM collected tissue samples. JH and QH performed IHC-related assays. CL and QH performed the flow cytometry analysis, while JX carried out the TCGA data set analysis.

  • Funding This study was jointly funded by the National Science Foundation for Distinguished Young Scholars of China (no 81625016), the National Natural Science Foundation of China (no 81602085 and 81902428) and the Shanghai Sailing Program (no 17YF1402500 and 19YF1409400).

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Ethics approval This study was approved by the Institutional Research Ethics Committee of Fudan University Shanghai Cancer Center (FUSCC), and written informed consent was obtained from all patients prior to the investigation. All animal experiments were performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of Fudan University, and were approved by the Institutional Animal Care and Use Committee of Fudan University.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement All data relevant to the study are included in the article or uploaded as supplementary information.

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