title: Loss of NDRG2 Expression Confers Oral Squamous Cell Carcinoma with Enhanced Metastatic Potential.
abstract: Loss of the tumor suppressor NDRG2 has been implicated in the development of oral squamous cell carcinoma (OSCC), acting by modulating PI3K/AKT-mediated dephosphorylation of PTEN at S380/S382/T383 (STT). Here, we show that the majority of OSCC tumors with lymph node metastasis, a major prognostic factor, exhibit high levels of phosphorylated AKT-S473 and PTEN-STT and low levels of NDRG2 expression. InNdrg2-deficient mice, which develop a wide range of tumors, we developed a model of OSCC by treatment with the tobacco surrogate 4-nitroquinoline-1-oxide (4-NQO). In this model, both the number and size of OSCC tumors were increased significantly byNdrg2deficiency, which also increased invasion of cervical lymph nodes. 4-NQO treatment of human OSCC cell lines exhibiting low NDRG2 expression induced epithelial-mesenchymal transition via activation of NF-κB signaling. Conversely, ectopic expression of NDRG2 reversed the EMT phenotype and inhibited NF-κB signaling via suppression of PTEN-STT and AKT-S473 phosphorylation. Our results show how NDRG2 expression serves as a critical determinant of the invasive and metastatic capacity of OSCC.Cancer Res; 77(9); 2363-74. ©2017 AACR.
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.|Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Tomonaga
authors.initials: T
authors.lastname: Ichikawa
authors.affiliation: Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Shingo
authors.initials: S
authors.lastname: Nakahata
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Yudai
authors.initials: Y
authors.lastname: Kondo
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Tagawa
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Nagai
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Baba
authors.affiliation: Laboratory of Veterinary Pathology, Department of Veterinary, Faculty of Agriculture, University of Miyazaki, Miyazaki, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yamaguchi
authors.affiliation: Department of Molecular Toxicology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
authors.forename: Mitsuru
authors.initials: M
authors.lastname: Futakuchi
authors.affiliation: Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Division of Tumor and Cellular Biochemistry, Department of Medical Sciences, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan. kmorishi@med.miyazaki-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Morishita
mesh_terms: D015112:4-Nitroquinoline-1-oxide / Q000633:toxicity; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008207:Lymphatic Metastasis / Q000235:genetics* / Q000473:pathology; D051379:Mice; D009062:Mouth Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D016328:NF-kappa B / Q000235:genetics; D051058:Oncogene Protein v-akt / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D015112:4-Nitroquinoline-1-oxide; D048868:Adaptor Proteins, Signal Transducing; D016328:NF-kappa B; D051058:Oncogene Protein v-akt; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D011506:Proteins; C485172:Ndr2 protein, mouse; C494929:PTEN protein, human