4.7 Article

MiR-422a regulates cellular metabolism and malignancy by targeting pyruvate dehydrogenase kinase 2 in gastric cancer

Journal

CELL DEATH & DISEASE
Volume 9, Issue -, Pages -

Publisher

NATURE PUBLISHING GROUP
DOI: 10.1038/s41419-018-0564-3

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Funding

  1. National Natural Science Foundation of China [81572362]
  2. National Natural Science Foundation Project of International Cooperation (NSFC-NIH) [81361120398]
  3. Primary Research and Development Plan of Jiangsu Province [BE2016786]
  4. Program for Development of Innovative Research Team in the First Affiliated Hospital of NJMU
  5. Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD) [JX10231801]
  6. 333 Project of Jiangsu Province [BRA2015474]
  7. Jiangsu Key Medical Discipline (General Surgery) [ZDXKA2016005]
  8. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University

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Increasing evidence indicates that dysregulation of microRNAs (miRNAs) plays a crucial role in human malignancies. Here, we showed that microRNA-422a (miR-422a) expression was dramatically downregulated in gastric cancer (GC) samples and cell lines compared with normal controls, and that its expression level was inversely related to tumor size and depth of infiltration. Functional studies revealed that the overexpression of miR-422a in GC tumor cells suppressed cell proliferation and migration, and drove a metabolic shift from aerobic glycolysis to oxidative phosphorylation. Mechanistic analysis suggested that miR-422a repressed pyruvate dehydrogenase kinase 2 (PDK2) to restore activity of the pyruvate dehydrogenase (PDH), the gatekeeping enzyme that catalyzes the decarboxylation of pyruvate to produce acetyl-CoA. Importantly, we further demonstrated that the mir-422a-PDK2 axis also influenced another metabolic pathway, de novo lipogenesis in cancer cells, and that it subseguently affected reactive oxygen species (ROS) and RB phosphorylation levels, ultimately resulting in cell cycle arrest in G1 phase. Our findings show that the miR-422a-PDK2 axis is an important mediator in metabolic reprogramming and a promising therapeutic target for antitumor treatment.

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