Epithelial membrane protein 1 promotes tumor metastasis by enhancing cell migration via copine-III and Rac1.
Epithelial membrane protein 1 promotes tumor metastasis by enhancing cell migration via copine-III and Rac1.
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DOI：
10.1038/s41388-018-0286-0
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发表时间：
2018-10
期刊：
影响因子：
8
通讯作者：
Ogita H
中科院分区：
文献类型：
--
作者：
Ahmat Amin MKB;Shimizu A;Zankov DP;Sato A;Kurita S;Ito M;Maeda T;Yoshida T;Sakaue T;Higashiyama S;Kawauchi A;Ogita H
肿瘤转移是癌症死亡的最常见原因。因此，阐明肿瘤转移的机制对于开发新的、有效的抗癌疗法以降低癌症死亡率是重要的。肿瘤微环境中癌细胞与周围基质细胞之间的相互作用是肿瘤转移的关键因素。使用与人前列腺癌LNCaP细胞和原代人前列腺基质细胞的共培养测定系统，我们鉴定了上皮膜蛋白1（EMP 1）作为在癌细胞中表达升高的基因。将过表达EMP 1的LNCaP细胞（EMP 1-LNCaP细胞）原位注射到裸鼠前列腺中诱导淋巴结和肺转移，而对照LNCaP细胞则没有。EMP 1-LNCaP细胞的细胞运动性和Rac 1活性高于对照LNCaP细胞。这些结果也在其他癌细胞系中观察到。我们新发现的copine-III作为EMP 1的细胞内结合伴侣。敲低Copine-III减弱了EMP 1-LNCaP细胞中增加的细胞运动性和Rac 1活性。通过野生型copine-III的再表达，而不是不能与EMP 1相互作用的copine-III突变体的再表达，可以恢复EMP 1-LNCaP细胞中敲低copine-III后降低的细胞运动性和Rac 1活性，这表明EMP 1-copine-III相互作用的重要性。磷酸化和激活的Src和一个Rac鸟嘌呤核苷酸交换因子Vav 2被发现参与EMP 1诱导的增强细胞运动性和Rac 1激活。此外，EMP 1在从具有较高Gleason评分的患者获得的前列腺癌样品中高度表达。这些结果表明，EMP 1的上调显著增加癌细胞迁移，导致肿瘤转移，表明EMP 1可能作为肿瘤转移的正调节因子发挥重要作用。
Tumor metastasis is the most common cause of cancer death. Elucidation of the mechanism of tumor metastasis is therefore important in the development of novel, effective anti-cancer therapies to reduce cancer mortality. Interaction between cancer cells and surrounding stromal cells in the tumor microenvironment is a key factor in tumor metastasis. Using a co-culture assay system with human prostate cancer LNCaP cells and primary human prostate stromal cells, we identified epithelial membrane protein 1 (EMP1) as a gene with elevated expression in the cancer cells. The orthotopic injection of LNCaP cells overexpressing EMP1 (EMP1-LNCaP cells) into the prostate of nude mice induced lymph node and lung metastases, while that of control LNCaP cells did not. EMP1-LNCaP cells had higher cell motility and Rac1 activity than control LNCaP cells. These results were also observed in other lines of cancer cells. We newly identified copine-III as an intracellular binding partner of EMP1. Knockdown of copine-III attenuated the increased cell motility and Rac1 activity in EMP1-LNCaP cells. Reduced cell motility and Rac1 activity following knockdown of copine-III in EMP1-LNCaP cells were recovered by re-expression of wild-type copine-III, but not of a copine-III mutant incapable of interacting with EMP1, suggesting the importance of the EMP1–copine-III interaction. Phosphorylated and activated Src and a Rac guanine nucleotide exchange factor Vav2 were found to be involved in the EMP1-induced enhancement of cell motility and Rac1 activation. Moreover, EMP1 was highly expressed in prostate cancer samples obtained from patients with higher Gleason score. These results demonstrate that upregulation of EMP1 significantly increases cancer cell migration that leads to tumor metastasis, suggesting that EMP1 may play an essential role as a positive regulator of tumor metastasis.
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影响因子：
5.7
作者：
Bid HK;Roberts RD;Manchanda PK;Houghton PJ
通讯作者：
Houghton PJ
影响因子：
3.1
作者：
Martin, Tracey A.;Lane, Jane;Jiang, Wen G.
通讯作者：
Jiang, Wen G.
影响因子：
5.3
作者：
López-Lago, M;Lee, K;Bustelo, XR
通讯作者：
Bustelo, XR
影响因子：
4.4
作者：
Ben-Porath, I;Kozak, CA;Benvenisty, N
通讯作者：
Benvenisty, N
DOI：
10.4137/cgm.s11285
发表时间：
2014
期刊：
Cancer growth and metastasis
影响因子：
--
作者：
Goubran HA;Kotb RR;Stakiw J;Emara ME;Burnouf T
通讯作者：
Burnouf T