P75 neurotrophin receptor inhibits invasion and metastasis of gastric cancer
P75 neurotrophin receptor inhibits invasion and metastasis of gastric cancer
复制标题
p75 神经营养素受体抑制胃癌的侵袭和转移。
DOI：
10.1158/1541-7786.mcr-06-0407
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发表时间：
2007-05-01
影响因子：
5.2
通讯作者：
Fan, Daiming
中科院分区：
文献类型：
--
作者：
Jin, Haifeng;Pan, Yanglin;Fan, Daiming
p75神经营养因子受体（p75 NTR）是目前研究的热点。然而，其在胃癌中的功能尚未阐明。本研究旨在探讨其与胃癌转移的关系。免疫组化结果显示，转移性胃癌中p75 NTR阳性表达率为15.09%（16/106），低于非转移性胃癌（64.15%; 68/106）。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 vs 0.23 ± 0.18; P < 0.01）。Western blotting结果显示，p75 NTR蛋白在高肝转移胃癌细胞系XGC 9811-L中的表达水平较低。通过降低尿激酶型纤溶酶原激活物（uPA）和基质金属蛋白酶（MMP）-9蛋白，增加基质金属蛋白酶组织抑制剂（TIMP）-1蛋白，显著抑制胃癌细胞株SGC 7901和MKN 45的体外粘附、侵袭、迁移和体内转移能力。进一步研究表明p75 NTR可抑制核因子-κ B（NF-κ B）信号。NF-κ B B特异性抑制剂SN 50可抑制胃癌细胞的体外侵袭和迁移能力，降低uPA和MMP 9蛋白的表达，增加TIMP 1蛋白的表达。p75 NTR具有抑制胃癌细胞侵袭和转移的作用，其机制至少部分是通过NF-κ B B信号转导途径下调uPA和MMP 9蛋白，上调TIMP 1蛋白而实现的。本研究提示p75 NTR可能成为转移性胃癌治疗的新靶点。
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 metal loprotei nase (MMP)-9 proteins and by increasing tissue inhibitor of matrix metal loproteinase (TIMP)-1 protein. Further studies showed that p75NTR could suppress the nuclear factor-kappa B (NF-kappa B) signal. SN50, a specific inhibitor of NF-kappa B, 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-kappa B signal transduction pathway. Our studies suggested that p75NTR may be used as a new potential therapeutic target in metastatic gastric cancer.