Division of Oral and Maxillofacial Surgery, Medicine of Sensory and Motor Organs, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki-gun, Miyazaki 889-1692, Japan.
Biochem Biophys Res Commun. 2010 Jan 22;391(4):1785-91. doi: 10.1016/j.bbrc.2009.12.156. Epub 2010 Jan 5.
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.
口腔癌是全球最常见的癌症之一，而鳞状细胞癌（OSCC）是口腔癌最常见的表型。尽管 OSCC 患者的生存率较差，且转移发生率较高，但 OSCC 发生的分子机制尚未阐明。本研究探讨了 N- MYC 下游调节基因 2（NDRG2）是否有助于 OSCC 的发生，因为据报道，NDRG2 是多种癌症的候选抑癌基因。大多数 OSCC 病例和一些伴有异型增生的癌前白斑病例中，NDRG2 mRNA 的下调依赖于启动子甲基化。在 HSC-3/OSCC 细胞系中诱导 NDRG2 表达可显著抑制细胞增殖并降低软琼脂上集落形成能力。大多数 OSCC 细胞系表现出 PI3K/Akt 信号通路的激活，而在 HSC-3 细胞中强制表达 NDRG2 可降低丝氨酸 473 处磷酸化 Akt（p-Akt）的水平。在 56.5%的 OSCC 肿瘤中检测到 p-Akt 的免疫组化染色，80.4%的肿瘤中未检测到 NDRG2 染色。此外，在分化程度为中-差的 OSCC 肿瘤中，阳性 p-Akt 染色与 NDRG2 表达降低呈负相关（p<0.005）。因此，NDRG2 是 OSCC 发展的候选抑癌基因，可能通过调节 Akt 信号通路部分促进 OSCC 的发生。
