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NDRG2 is a candidate tumor-suppressor for oral squamous-cell carcinoma
Hiroshi Furuta1, Yuudai Kondo, Shingo Nakahata
1Division of Oral and Maxillofacial Surgery, Medicine of Sensory and Motor Organs, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki-gun, Miyazaki 889-1692, Japan.
Abstract:
Oral cancer is one of the most common cancers worldwide, and squamous-cell carcinoma (OSCC) is the most common phenotype of oral cancer. Although patients with OSCC have poor survival rates and a high incidence of metastasis, the molecular mechanisms of OSCC development have not yet been elucidated. This study investigated whether N-myc downstream-regulated gene 2 (NDRG2) contributes to the carcinogenesis of OSCC, as NDRG2 is reported to be a candidate tumor-suppressor gene in a wide variety of cancers. The down-regulation of NDRG2 mRNA, which was dependent on promoter methylation, was seen in the majority of OSCC cases and in several cases of precancerous leukoplakia with dysplasia. Induction of NDRG2 expression in an HSC-3/OSCC cell line significantly inhibited cell proliferation and decreased colony formation ability on soft agar. The majority of OSCC cell lines showed an activation of PI3K/Akt signaling, and enforced expression of NDRG2 in HSC-3 cells decreased the level of phosphorylated Akt at Serine 473 (p-Akt). Immunohistochemical p-Akt staining was detected in 56.5% of the OSCC tumors, and 80.4% of the tumors were negative for NDRG2 staining. Moreover, positive p-Akt staining was inversely correlated with decreased NDRG2 expression in OSCC tumors with moderate to poor differentiation (p<0.005). Therefore, NDRG2 is a candidate tumor-suppressor gene for OSCC development and probably contributes to the tumorigenesis of OSCC partly via the modulation of Akt signaling.
Insights
N-myc downstream-regulated gene 2 (NDRG2) acts as a tumor suppressor in oral squamous-cell carcinoma (OSCC). Its down-regulation, linked to promoter methylation, inhibits OSCC cell growth and Akt signaling, suggesting NDRG2
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Oral cancer, particularly oral squamous-cell carcinoma (OSCC), presents poor survival rates and high metastatic potential.
- The underlying molecular mechanisms driving OSCC development remain incompletely understood.
- N-myc downstream-regulated gene 2 (NDRG2) is recognized as a potential tumor suppressor in various cancers.
Purpose of the Study:
- To investigate the role of NDRG2 in the carcinogenesis of OSCC.
- To determine if NDRG2 functions as a tumor suppressor in oral cancer.
- To explore the relationship between NDRG2 expression and Akt signaling in OSCC.
Main Methods:
- Analysis of NDRG2 mRNA expression and promoter methylation in OSCC tissues and cell lines.
- Assessment of NDRG2's impact on cell proliferation and colony formation in OSCC cells.
- Evaluation of Akt signaling pathway activation and its correlation with NDRG2 expression in OSCC tumors.
Main Results:
- NDRG2 mRNA down-regulation, associated with promoter methylation, was observed in most OSCC cases and some precancerous lesions.
- Restoring NDRG2 expression in OSCC cells significantly reduced proliferation and anchorage-independent growth.
- NDRG2 expression inversely correlated with phosphorylated Akt (p-Akt) levels in OSCC, particularly in poorly differentiated tumors.
Conclusions:
- NDRG2 functions as a tumor suppressor gene in oral squamous-cell carcinoma.
- NDRG2 down-regulation, driven by promoter methylation, contributes to OSCC development.
- NDRG2 likely modulates tumorigenesis in OSCC, partly through the regulation of Akt signaling.
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