RT Journal Article
SR Electronic
T1 Localisation of PGK1 determines metabolic phenotype to balance metastasis and proliferation in patients with SMAD4-negative pancreatic cancer
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP 888
OP 900
DO 10.1136/gutjnl-2018-317163
VO 69
IS 5
A1 Chen Liang
A1 Si Shi
A1 Yi Qin
A1 Qingcai Meng
A1 Jie Hua
A1 Qiangshen Hu
A1 Shunrong Ji
A1 Bo Zhang
A1 Jin Xu
A1 Xian-Jun Yu
YR 2020
UL http://gut.bmj.com/content/69/5/888.abstract
AB 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.