Cdc42 subcellular relocation in response to VEGF/NRP1 engagement is associated with the poor prognosis of colorectal cancer
Cdc42 subcellular relocation in response to VEGF/NRP1 engagement is associated with the poor prognosis of colorectal cancer
复制标题
响应 VEGF/NRP1 接合的 Cdc42 亚细胞重定位与结直肠癌的不良预后相关
DOI：
10.1038/s41419-020-2370-y
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发表时间：
2020-03-05
影响因子：
9
通讯作者：
Deng, Yong-jian
中科院分区：
文献类型：
--
作者：
Ma, Li-li;Guo, Li-li;Deng, Yong-jian
恶性肿瘤的显微镜指示和癌症的标志分子对于确定癌症患者预后和随后的医疗干预至关重要。在这里，我们发现，相比顶端表达的Cdc 42，这表明，基底表达的Cdc 42发生在迁移细胞的前端，腺基底表达的Cdc 42（细胞分裂周期42）在组织中表示较差的结直肠癌（CRC）患者的预后。目前的研究表明，激活Cdc 42被迅速招募到迁移CRC细胞前VEGF刺激后，通过参与膜锚定神经纤毛蛋白-1（NRP 1）。当用NRP 1敲低或ATWLPPR（A7R，VEGF/NRP 1相互作用的拮抗剂）阻断VEGF信号传导时，Cdc 42活化和向细胞前的重新定位被减弱，丝状伪足和侵入伪足的形成被抑制。VEGF/NRP 1轴通过Cdc 42激活和膜突起延伸的肌动蛋白丝聚合引起的重新定位来调节定向迁移、侵袭和转移。总的来说，亚细胞Cdc 42在细胞前沿的免疫微形态学模式表明CRC患者的侵袭性行为和预后不良。破坏VEGF/NRP 1轴或Cdc 42重新定位的细胞内和细胞外相互作用可以在临床实践中进行，因为它可能抑制癌细胞运动和转移。
Microscopic indications of malignancy and hallmark molecules of cancer are pivotal to determining cancer patient prognosis and subsequent medical intervention. Here, we found that compared to apical expression of Cdc42, which indicated that basal expression of Cdc42 occurred at the migrating cell front, glandular basal expression of Cdc42 (cell division cycle 42) in tissues indicated poorer prognoses for colorectal cancer (CRC) patients. The current study shows that activated Cdc42 was rapidly recruited to the migrating CRC cell front after VEGF stimulation through engagement of membrane-anchored neuropilin-1 (NRP1). When VEGF signalling was blocked with NRP1 knockdown or ATWLPPR (A7R, antagonist of VEGF/NRP1 interaction), Cdc42 activation and relocation to the cell front was attenuated, and filopodia and invadopodia formation was inhibited. The VEGF/NRP1 axis regulates directional migration, invasion, and metastasis through Cdc42 activation and relocation resulting from actin filament polymerisation of the extensions of membrane protrusions. Collectively, the immuno-micromorphological pattern of subcellular Cdc42 at the cell front indicated aggressive behaviours and predicted poor prognosis in CRC patients. Disruption of the intra- and extracellular interactions of the VEGF/NRP1 axis or Cdc42 relocation could be performed in clinical practice because it might inhibit cancer cell motility and metastasis.