title: Regulatory circuit of PKM2/NF-κB/miR-148a/152-modulated tumor angiogenesis and cancer progression.
abstract: Upregulation of the embryonic M2 isoform of pyruvate kinase (PKM2) emerges as a critical player in the cancer development and metabolism, yet the underlying mechanism of PKM2 overexpression remains to be elucidated. Here we demonstrate that IGF-1/IGF-IR regulates PKM2 expression by enhancing HIF-1α-p65 complex binding to PKM2 promoter. PKM2 expression is regulated by miR-148a/152 suppression. PKM2 directly interacts with NF-κB p65 subunit to promote EGR1 expression for regulating miR-148a/152 feedback circuit in normal cells, but not in cancer cells because of the DNA hypermethylation of miR-148a and miR-152 gene promoters. The silencing of miR-148a/152 contributes to the overexpression of PKM2, NF-κB or/and IGF-IR in some cancer cells. We show that disruption of PKM2/NF-κB/miR-148a/152 feedback loop can regulate cancer cell growth and angiogenesis, and is also associated with triple-negative breast cancer (TNBC) phenotype, which may have clinical implication for providing novel biomarker(s) of TNBC and potential therapeutic target(s) in the future.
authors.affiliation: State Key lab of Reproductive Medicine, Department of Pathology, Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: L-Z
authors.initials: LZ
authors.lastname: Liu
authors.affiliation: State Key lab of Reproductive Medicine, Department of Pathology, Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, China.|Department of Pathology, Anhui Medical University, Hefei, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Yin
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: J
authors.initials: J
authors.lastname: He
authors.affiliation: State Key lab of Reproductive Medicine, Department of Pathology, Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, China.
authors.forename: Q
authors.initials: Q
authors.lastname: Li
authors.affiliation: State Key lab of Reproductive Medicine, Department of Pathology, Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, China.
authors.forename: X
authors.initials: X
authors.lastname: Qian
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China.
authors.forename: Y
authors.initials: Y
authors.lastname: You
authors.affiliation: Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Z
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: S C
authors.initials: SC
authors.lastname: Peiper
authors.affiliation: Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, China.
authors.forename: Y
authors.initials: Y
authors.lastname: Shu
authors.affiliation: State Key lab of Reproductive Medicine, Department of Pathology, Collaborative Innovation Center for Cancer Personalized Medicine, Cancer Center, Nanjing Medical University, Nanjing, China.|Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: B-H
authors.initials: BH
authors.lastname: Jiang
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D051766:Early Growth Response Protein 1 / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D016328:NF-kappa B / Q000235:genetics*; D009389:Neovascularization, Pathologic / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D013963:Thyroid Hormones / Q000235:genetics*; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D015854:Up-Regulation / Q000235:genetics; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; D051766:Early Growth Response Protein 1; D008565:Membrane Proteins; D035683:MicroRNAs; D016328:NF-kappa B; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C497325:EGR1 protein, human; C550570:MIRN148 microRNA, human; C550856:MIRN152 microRNA, human