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Loss of NDRG2 Expression Confers Oral Squamous Cell Carcinoma with Enhanced Metastatic Potential
Tomohiro Tamura1,2, Tomonaga Ichikawa2, Shingo Nakahata2
1Division of Oral and Maxillofacial Surgery, Department of Medicine of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.
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.
Insights
Loss of NDRG2 (N-myc downstream regulated gene 2) promotes oral squamous cell carcinoma (OSCC) invasion and metastasis. Restoring NDRG2 inhibits tumor growth and spread by suppressing key signaling pathways.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Loss of the tumor suppressor NDRG2 is linked to oral squamous cell carcinoma (OSCC) development.
- NDRG2 influences the PI3K/AKT pathway, affecting PTEN phosphorylation at specific sites (S380/S382/T383).
- High phosphorylated AKT-S473 and PTEN-STT levels, with low NDRG2, correlate with lymph node metastasis in OSCC.
Purpose of the Study:
- To investigate the role of NDRG2 in OSCC invasion and metastasis.
- To elucidate the molecular mechanisms by which NDRG2 loss promotes OSCC progression.
- To evaluate NDRG2's potential as a therapeutic target in OSCC.
Main Methods:
- Utilized a 4-nitroquinoline-1-oxide (4-NQO) induced OSCC mouse model in Ndrg2-deficient mice.
- Analyzed human OSCC cell lines with varying NDRG2 expression levels.
- Investigated signaling pathways including PI3K/AKT, PTEN, and NF-κB.
Main Results:
- Ndrg2 deficiency significantly increased OSCC tumor number, size, and lymph node invasion in mice.
- Low NDRG2 expression in OSCC cells promoted epithelial-mesenchymal transition (EMT) via NF-κB activation.
- Ectopic NDRG2 expression reversed EMT and inhibited NF-κB signaling by suppressing PTEN-STT and AKT-S473 phosphorylation.
Conclusions:
- NDRG2 expression is a critical determinant of OSCC invasiveness and metastatic potential.
- NDRG2 loss promotes OSCC progression through activation of AKT/PTEN and NF-κB signaling pathways.
- Restoring NDRG2 function may offer a therapeutic strategy to inhibit OSCC metastasis.
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