Jin Haifeng, Pan Yanglin, He Lijie, Zhai Huihong, Li Xiaohua, Zhao Lina, Sun Li, Liu Jie, Hong Liu, Song Jiugang, Xie Huahong, Gao Juan, Han Shuang, Li Ying, Fan Daiming
State Key Laboratory of Cancer Biology and Institute of Digestive Diseases, Xijing Hospital, the Fourth Military Medical University, 17 Changle Western Road, Xi'an 710032, Shaanxi Province, P.R. China.
Mol Cancer Res. 2007 May;5(5):423-33. doi: 10.1158/1541-7786.MCR-06-0407.
The p75 neurotrophin receptor (p75NTR) is a focus for study at present. However, its function in gastric cancer was not elucidated. Here, we investigated its relation with metastasis of gastric cancer. By immunohistochemistry, we found that the positive rate of p75NTR expression in metastatic gastric cancer was 15.09% (16 of 106), which was lower compared with nonmetastatic gastric cancer (64.15%; 68 of 106). The average staining score in nonmetastatic gastric cancer was significantly higher than in metastatic gastric cancer (1.21 +/- 0.35 versus 0.23 +/- 0.18; P<0.01). p75NTR protein level was also lowly expressed in the highly liver-metastatic gastric cancer cell line XGC9811-L compared with other gastric cancer cell lines by Western blotting. It could also significantly inhibit the in vitro adhesive, invasive, and migratory and in vivo metastatic abilities of gastric cancer cell lines SGC7901 and MKN45 by reducing urokinase-type plasminogen activator (uPA) and matrix metalloproteinase (MMP)-9 proteins and by increasing tissue inhibitor of matrix metalloproteinase (TIMP)-1 protein. Further studies showed that p75NTR could suppress the nuclear factor-kappaB (NF-kappaB) signal. SN50, a specific inhibitor of NF-kappaB, which could inhibit in vitro invasive and migratory abilities of gastric cancer cells, reduced expression of uPA and MMP9 proteins and increased expression of TIMP1 protein. Taken together, p75NTR had the function of inhibiting the invasive and metastatic abilities of gastric cancer cells, which was mediated, at least partially, by down-regulation of uPA and MMP9 proteins and up-regulation of TIMP1 protein via the NF-kappaB signal transduction pathway. Our studies suggested that p75NTR may be used as a new potential therapeutic target in metastatic gastric cancer.
p75神经营养因子受体（p75NTR）是目前的研究热点。然而，其在胃癌中的功能尚未阐明。在此，我们研究了其与胃癌转移的关系。通过免疫组织化学，我们发现转移性胃癌中p75NTR表达的阳性率为15.09%（106例中的16例），与非转移性胃癌（64.15%；106例中的68例）相比更低。非转移性胃癌的平均染色评分显著高于转移性胃癌（1.21±0.35对0.23±0.18；P<0.01）。通过蛋白质印迹法检测发现，与其他胃癌细胞系相比，高肝转移胃癌细胞系XGC9811-L中的p75NTR蛋白水平也低表达。它还可通过降低尿激酶型纤溶酶原激活剂（uPA）和基质金属蛋白酶（MMP）-9蛋白水平以及增加基质金属蛋白酶组织抑制剂（TIMP）-1蛋白水平，显著抑制胃癌细胞系SGC7901和MKN45的体外黏附、侵袭、迁移及体内转移能力。进一步研究表明，p75NTR可抑制核因子-κB（NF-κB）信号。NF-κB的特异性抑制剂SN50可抑制胃癌细胞的体外侵袭和迁移能力，降低uPA和MMP9蛋白的表达，并增加TIMP1蛋白的表达。综上所述，p75NTR具有抑制胃癌细胞侵袭和转移能力的功能，这至少部分是通过NF-κB信号转导途径下调uPA和MMP9蛋白以及上调TIMP1蛋白介导的。我们的研究提示，p75NTR可能作为转移性胃癌新的潜在治疗靶点。
