Kim Aeyung, Kim Myung-Jin, Yang Young, Kim Jae Wha, Yeom Young Il, Lim Jong-Seok
Department of Biological Science and Research Center for Women's Diseases, Sookmyung Women's University, Chungpa-Dong, Yongsan-Gu, Seoul, Republic of Korea.
Carcinogenesis. 2009 Jun;30(6):927-36. doi: 10.1093/carcin/bgp072. Epub 2009 Mar 31.
Downregulation of the N-myc downstream-regulated gene 2 (NDRG2) gene is involved in the progression of aggressive forms of cancer, along with the poor prognosis of cancer patients. In the current study, we examined the effect of NDRG2 expression on the metastatic potential of HT1080 human fibrosarcoma and B16F10 murine melanoma cells in both in vitro and in vivo systems. In gelatin zymography, NDRG2 expression remarkably suppressed the matrix metalloproteinase (MMP)-9 activity and slightly inhibited MMP-2 activity of both cell lines. Tumor migration and invasion in vitro were significantly reduced by NDRG2 expression, and NDRG2 inhibited tumor cell proliferation in an anchorage-independent semisolid agar assay. Specifically, we found that NDRG2 affects invasion through suppression of nuclear factor kappa B (NF-kappaB) activity. In animal experiments, subcutaneously injected B16F10-NDRG2 cells showed delayed tumor growth compared with B16F10-mock cells. Furthermore, severe metastasis from primary tumor mass into the draining lymph nodes was observed after injection of B16F10-mock cells, but not with B16F10-NDRG2 cells. Pulmonary metastasis after intravenous injection of B16F10 cells was also reduced by NDRG2 expression. Intra- and peritumoral angiogenesis that is critical for the tumor growth and metastasis was clearly found in tumors after injection with B16F10-mock cells, whereas it was impaired in tumors after injection with B16F10-NDRG2 cells. Collectively, our data show that NDRG2 expression significantly suppresses tumor invasion by inhibiting MMP activities, which are regulated through the NF-kappaB signaling. Moreover, results from animal experiments provide evidence for the regulatory role of the NDRG2 gene in metastatic tumors.
N - myc下游调控基因2（NDRG2）基因的下调与侵袭性癌症的进展以及癌症患者的不良预后有关。在本研究中，我们在体外和体内系统中研究了NDRG2表达对HT1080人纤维肉瘤和B16F10小鼠黑色素瘤细胞转移潜能的影响。在明胶酶谱分析中，NDRG2表达显著抑制了两种细胞系的基质金属蛋白酶（MMP）-9活性，并轻微抑制了MMP-2活性。NDRG2表达显著降低了体外肿瘤的迁移和侵袭，并且在非锚定依赖的半固体琼脂试验中，NDRG2抑制了肿瘤细胞增殖。具体而言，我们发现NDRG2通过抑制核因子κB（NF-κB）活性影响侵袭。在动物实验中，皮下注射的B16F10 - NDRG2细胞与B16F10 - mock细胞相比，肿瘤生长延迟。此外，注射B16F10 - mock细胞后观察到原发肿瘤块向引流淋巴结的严重转移，但注射B16F10 - NDRG2细胞后未观察到。NDRG2表达也降低了静脉注射B16F10细胞后的肺转移。在注射B16F10 - mock细胞后的肿瘤中清楚地发现了对肿瘤生长和转移至关重要的瘤内和瘤周血管生成，而在注射B16F10 - NDRG2细胞后的肿瘤中则受损。总体而言，我们的数据表明，NDRG2表达通过抑制MMP活性显著抑制肿瘤侵袭，而MMP活性是通过NF-κB信号传导调节的。此外，动物实验结果为NDRG2基因在转移性肿瘤中的调节作用提供了证据。
