Expression of aquaporin 5 (AQP5) promotes tumor invasion in human non small cell lung cancer.
Expression of aquaporin 5 (AQP5) promotes tumor invasion in human non small cell lung cancer.
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DOI：
10.1371/journal.pone.0002162
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发表时间：
2008-05-14
期刊：
影响因子：
3.7
通讯作者：
Moon C
中科院分区：
文献类型：
--
作者：
Chae YK;Woo J;Kim MJ;Kang SK;Kim MS;Lee J;Lee SK;Gong G;Kim YH;Soria JC;Jang SJ;Sidransky D;Moon C
水通道蛋白（AQP）是水通道蛋白，在跨细胞和跨上皮水运动中发挥重要作用。近年来，AQP 在人类癌变中的作用已成为人们极大兴趣的领域。在此，通过免疫组织化学 (IHC)，我们发现 35.3%（IHC 评分：≥1, 144/408）的切除 NSCLC 组织样本中存在 AQP5 蛋白表达。 AQP5 阳性状态（IHC 评分：≥2）的 NSCLC 病例的肿瘤复发率高于阴性病例（54.7% vs. 35.1%，p = 0.005），且无病生存率较差（p = 0.033；OR = 1.52；95%CI：1.04−2.23）。使用稳定转染全长野生型 AQP5 (AQP5) 及其两个突变体（阻断膜运输的 N185D 和阻断 Ser156 磷酸化的 S156A）的 BEAS-2B 和 NIH3T3 细胞进行的进一步体外侵袭测定表明，AQP5 诱导细胞侵袭，而两种突变体则不诱导细胞侵袭。在 BEAS-2B 细胞中，AQP5 的表达引起纺锤样和成纤维细胞形态变化以及细胞间接触和细胞极性的丧失。只有具有 AQP5 的细胞（而不是两个突变体中的任何一个）表现出上皮细胞标记物的丢失和间充质细胞标记物的增加。在人 SH3 结构域蛋白阵列中，来自 BEAS-2B 和 AQP5 的细胞提取物显示出与 c-Src、Lyn 和 Grap2 C 末端的 SH3 结构域的强大结合活性。此外，在免疫沉淀测定中，与 N185D 或 S156A 突变体相比，在 Tyr416 上磷酸化的活化 c-Src 显示出与带有 AQP5 的 BEAS-2B 细胞提取物更强的结合活性。荧光原位杂交 (FISH) 分析未能显示基因组扩增的证据，表明 AQP5 表达是次要事件。基于这些临床和分子观察，我们得出结论，AQP5通过Ser156的磷酸化以及随后与c-Src的相互作用，在NSCLC侵袭中发挥重要作用，因此可能为开发NSCLC的新治疗靶点和预后标志物提供独特的机会。
The aquaporins (AQP) are water channel proteins playing a major role in transcellular and transepithelial water movement. Recently, the role of AQPs in human carcinogenesis has become an area of great interest. Here, by immunohistochemistry (IHC), we have found an expression of AQP5 protein in 35.3% (IHC-score: ≥1, 144/408) of the resected NSCLC tissue samples. Cases with AQP5-positive status (IHC-score: ≥2) displayed a higher rate of tumor recurrence than negative ones in NSCLC (54.7% vs. 35.1%, p = 0.005) and worse disease-free survival (p = 0.033; OR = 1.52; 95%CI:1.04−2.23). Further in vitro invasion assay using BEAS-2B and NIH3T3 cells stably transfected with overexpression constructs for full length wild-type AQP5 (AQP5) and its two mutants, N185D which blocks membrane trafficking and S156A which blocks phosphorylation on Ser156, showed that AQP5 induced cell invasions while both mutants did not. In BEAS-2B cells, the expression of AQP5 caused a spindle-like and fibroblastic morphologic change and losses of cell-cell contacts and cell polarity. Only cells with AQP5, not either of two mutants, exhibited a loss of epithelial cell markers and a gain of mesenchymal cell markers. In a human SH3-domains protein array, cellular extracts from BEAS-2B with AQP5 showed a robust binding activity to SH3-domains of the c-Src, Lyn, and Grap2 C-terminal. Furthermore, in immunoprecipitation assay, activated c-Src, phosphorylated on Tyr416, showed a stronger binding activity to cellular extracts from BEAS-2B with AQP5 compared with N185D or S156A mutant. Fluorescence in situ hybridization (FISH) analysis failed to show evidence of genomic amplification, suggesting AQP5 expression as a secondary event. Based on these clinical and molecular observations, we conclude that AQP5, through its phosphorylation on Ser156 and subsequent interaction with c-Src, plays an important role in NSCLC invasion and, therefore, may provide a unique opportunity for developing a novel therapeutic target as well as a prognostic marker in NSCLC.
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影响因子：
2.9
作者：
KE, Y;REDDEL, RR;HARRIS, CC
通讯作者：
HARRIS, CC
影响因子：
2.7
作者：
Avizienyte, E;Brunton, VG;Frame, MC
通讯作者：
Frame, MC
影响因子：
6.6
作者：
Kageyama, Y;Sasaki, S;Ikawa, Y
通讯作者：
Ikawa, Y
影响因子：
8
作者：
Moon, C;Soria, JC;Mao, L
通讯作者：
Mao, L
DOI：
10.1016/s0022-5223(99)70294-1
发表时间：
1999-04-01
影响因子：
6
作者：
D'Amico, TA;Massey, M;Harpole, DH
通讯作者：
Harpole, DH