PLoS Biol：恶性胶质瘤扩散的新靶点NKCC1

近日，约翰霍普金斯大学的研究者发现了一种可以运送钠离子、钾离子和氯化物的蛋白质，该蛋白质可以为恶性胶质瘤（一种常见的致命的脑癌）如何迁移以及侵入健康大脑组织提供一定线索。相关研究成果刊登在了近日的国际杂志PLoS Biology上。研究文章中，作者指出，目前市场上一种便宜的FDA批准的药品就可以用于减缓恶性胶质瘤细胞的转移速度。

研究者Alfredo Quinones Hinojosa表示，目前对于脑癌最大的难点和挑战就是如何控制癌细胞的转移，目前我们无法控制；如果在癌细胞进入正常脑组织之前我们可以将其捕获的话，我们就可以更好地去控制恶性胶质瘤细胞，并且提高患者的生存质量。

每年在美国大概会诊断出10000个恶性胶质瘤患者，在发现疾病15个月之后，恶性胶质瘤便会剧烈发病并且会急剧缩短患者的寿命以及降低其生活质量。这种恶性胶质瘤细胞可以很快扩散到健康的大脑组织中，令目前的治疗措施无可奈何。研究者为了寻找阻止或者限制恶性胶质瘤扩散的速度并且阻止致死的再发生，他们发现了一种肿瘤细胞蛋白NKCC1。这种蛋白质可以转移钠、钾和氯离子，并且可以调节细胞容量。

研究者如果细胞中含有大量的NKCC1，则细胞可以移动地更快，因为这种蛋白可以使得肿瘤细胞更容易地抓住其它大脑细胞或者大脑组织。肿瘤细胞中这种蛋白质越多，那么恶性胶质瘤细胞扩散的速度就越快。当NKCC1缺失时，细胞将会出现大面积的局部粘着斑，这将允许周围的细胞吸附至粘着斑上，大量的吸附将会导致细胞更加稳定地固定在某处。实验中，研究者封闭了此蛋白的功能，这能够有效的减缓肿瘤细胞的迁移；更慢的移动速度意味着更慢的侵袭速度。

为了封堵此途径，研究者使用了利尿剂布美他尼，一种可以减小肿块和液体滞留的普通药片；这种药物可以有效的封闭NKCC途径，达到减缓肿瘤细胞扩散的速度。研究者表示，如果肿瘤迁移速度降低的话，那么我们将很容易清除肿瘤细胞。而且研究者试图去将人类肿瘤的等级和NKCC1水平联系上，他们发现低侵袭性的肿瘤细胞中NKCC1的水平比较低，反之则很高。研究者最后表示，NKCC1蛋白不仅可以提高肿瘤细胞的扩散能力，而且也是临床诊断的一个重要标记物。

doi:​10.1371/journal.pbio.1001320
PMC:
PMID:

Regulation of Brain Tumor Dispersal by NKCC1 Through a Novel Role in Focal Adhesion Regulation

Tomas Garzon-Muvdi1, Paula Schiapparelli1, Colette ap Rhys1, Hugo Guerrero-Cazares1, Christopher Smith2, Deok-Ho Kim1,2,3, Lyonell Kone1, Harrison Farber1, Danielle Y. Lee4, Steven S. An4,5, Andre Levchenko2*, Alfredo Quiñones-Hinojosa1,6*

Glioblastoma (GB) is a highly invasive and lethal brain tumor due to its universal recurrence. Although it has been suggested that the electroneutral Na+-K+-Cl− cotransporter 1 (NKCC1) can play a role in glioma cell migration, the precise mechanism by which this ion transporter contributes to GB aggressiveness remains poorly understood. Here, we focused on the role of NKCC1 in the invasion of human primary glioma cells in vitro and in vivo. NKCC1 expression levels were significantly higher in GB and anaplastic astrocytoma tissues than in grade II glioma and normal cortex. Pharmacological inhibition and shRNA-mediated knockdown of NKCC1 expression led to decreased cell migration and invasion in vitro and in vivo. Surprisingly, knockdown of NKCC1 in glioma cells resulted in the formation of significantly larger focal adhesions and cell traction forces that were approximately 40% lower than control cells. Epidermal growth factor (EGF), which promotes migration of glioma cells, increased the phosphorylation of NKCC1 through a PI3K-dependant mechanism. This finding is potentially related to WNK kinases. Taken together, our findings suggest that NKCC1 modulates migration of glioma cells by two distinct mechanisms: (1) through the regulation of focal adhesion dynamics and cell contractility and (2) through regulation of cell volume through ion transport. Due to the ubiquitous expression of NKCC1 in mammalian tissues, its regulation by WNK kinases may serve as new therapeutic targets for GB aggressiveness and can be exploited by other highly invasive neoplasms.