title: The microRNA-182-PDK4 axis regulates lung tumorigenesis by modulating pyruvate dehydrogenase and lipogenesis.
abstract: Reprogrammed metabolism is one of the hallmarks of cancer. The dysregulation of glycolysis in cancer has been heavily studied. However, it remains largely unclear how other metabolic processes are regulated in cancer cells. Here we show that microRNA-182 (miR-182) suppresses pyruvate dehydrogenase (PDH) kinase 4 (PDK4) and promotes lung tumorigenesis. miR-182 is dysregulated and inversely correlated with PDK4 in human lung adenocarcinomas. The miR-182-PDK4 axis regulates lung cancer cell growth by modulating the activity of PDH, the gatekeeping enzyme of pyruvate flux into acetyl-CoA, and subsequently de novo lipogenesis of cancer cells. Suppression of lipogenesis by silencing ATP citrate lyase (ACLY) and fatty acid synthase (FASN) or by chemical inhibitors diminishes the effects of miR-182-PDK4 in tumor growth. Alteration of de novo lipogenesis also affects reactive oxygen species (ROS) production and the downstream JNK signaling pathway. Hence, our work suggests that the miR-182-PDK4 axis is a crucial regulator of cancer cell metabolism and a potential target for antitumor therapy.
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine; University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.affiliation: The Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: M
authors.initials: M
authors.lastname: Li
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine; University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Hu
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine; University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: R
authors.initials: R
authors.lastname: Lei
authors.affiliation: Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, China.
authors.forename: H
authors.initials: H
authors.lastname: Xiong
authors.affiliation: The State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: H
authors.initials: H
authors.lastname: Ji
authors.affiliation: The Key Laboratory of Food Safety Research, Institute for Nutritional Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: H
authors.identifier: 0000-0001-7049-1560
authors.initials: H
authors.lastname: Yin
authors.affiliation: Department of Pathology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Wei
authors.affiliation: The Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences & Shanghai Jiao Tong University School of Medicine; University of Chinese Academy of Sciences, Shanghai, China.
authors.forename: G
authors.initials: G
authors.lastname: Hu
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006019:Glycolysis; D006801:Humans; D050155:Lipogenesis; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009367:Neoplasm Staging; D010766:Phosphorylation; D011379:Prognosis; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011773:Pyruvates / Q000378:metabolism; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D035683:MicroRNAs; C538984:Mirn182 microRNA, human; C000631432:PDK4 protein, human; C000631439:Pdk4 protein, mouse; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D011773:Pyruvates; D017382:Reactive Oxygen Species; D017346:Protein Serine-Threonine Kinases