RRC ID 62782
Author Tamura T, Ichikawa T, Nakahata S, Kondo Y, Tagawa Y, Yamamoto K, Nagai K, Baba T, Yamaguchi R, Futakuchi M, Yamashita Y, Morishita K.
Title Loss of NDRG2 Expression Confers Oral Squamous Cell Carcinoma with Enhanced Metastatic Potential.
Journal Cancer Res
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. In Ndrg2-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 by Ndrg2 deficiency, 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.
Volume 77(9)
Pages 2363-2374
Published 2017-5-1
DOI 10.1158/0008-5472.CAN-16-2114
PII 0008-5472.CAN-16-2114
PMID 28209617
MeSH 4-Nitroquinoline-1-oxide / toxicity Adaptor Proteins, Signal Transducing Animals Carcinoma, Squamous Cell / chemically induced Carcinoma, Squamous Cell / genetics* Carcinoma, Squamous Cell / pathology Cell Line, Tumor Disease Models, Animal Epithelial-Mesenchymal Transition / drug effects Gene Expression Regulation, Neoplastic Humans Lymphatic Metastasis / genetics* Lymphatic Metastasis / pathology Mice Mouth Neoplasms / chemically induced Mouth Neoplasms / genetics* Mouth Neoplasms / pathology NF-kappa B / genetics Oncogene Protein v-akt / genetics PTEN Phosphohydrolase / genetics Phosphatidylinositol 3-Kinases / genetics Phosphorylation Proteins / genetics* Signal Transduction / drug effects
IF 9.727
Human and Animal Cells Ca9-22(RCB1976) HSC-2(RCB1945) HSC-4(RCB1902) Sa3(RCB0980) HSQ-89(RCB0789) SAS(RCB1974) HO-1-u-1(RCB2102)