Neuropilin-2 promotes tumourigenicity and metastasis in oesophageal squamous cell carcinoma through ERK-MAPK-ETV4-MMP-E-cadherin deregulation
Neuropilin-2 promotes tumourigenicity and metastasis in oesophageal squamous cell carcinoma through ERK-MAPK-ETV4-MMP-E-cadherin deregulation
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DOI：
10.1002/path.4728
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发表时间：
2016-07-01
影响因子：
7.3
通讯作者：
Ma, Stephanie
中科院分区：
文献类型：
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作者：
Fung, Tsun Ming;Ng, Kai Yu;Ma, Stephanie
食管鳞状细胞癌（ESCC）是食管癌最常见的组织学亚型。该疾病在中国南方尤为流行。其发病率呈上升趋势，总体生存率仍然很低。迫切需要鉴定和表征更好的用于早期检测和治疗靶向的分子标志物。在此，我们报道跨膜型和可溶性神经纤毛蛋白 - 2（NRP2）的水平在ESCC中显著上调，并且与肿瘤晚期、淋巴结转移、较差的R分类以及患者更差的总体生存呈正相关。ESCC中NRP2的上调部分是由于2号染色体q臂的基因扩增。NRP2过表达在体外促进了ESCC的克隆形成能力、血管生成和转移，而通过慢病毒敲低或中和抗体使NRP2沉默则产生相反的效果。这一发现在皮下致瘤性和尾静脉转移的动物模型体内得到了进一步验证。从机制上讲，NRP2的过表达诱导了ERK MAP激酶和转录因子ETV4的表达，导致MMP - 2和MMP - 9活性增强，进而抑制了E - 钙黏蛋白。总之，NRP2通过调节ERK - MAPK - ETV4 - MMP - E - 钙黏蛋白信号通路促进了ESCC的肿瘤发生和转移。NRP2是ESCC潜在的诊断或预后生物标志物以及治疗靶点。版权所有（C）2016英国和爱尔兰病理学会。由约翰威立父子有限公司出版。
Oesophageal squamous cell carcinoma (ESCC) is the most common histological subtype of oesophageal cancer. The disease is particularly prevalent in southern China. The incidence of the disease is on the rise and its overall survival rate remains dismal. Identification and characterization of better molecular markers for early detection and therapeutic targeting are urgently needed. Here, we report levels of transmembrane and soluble neuropilin-2 (NRP2) to be significantly up-regulated in ESCC, and to correlate positively with advanced tumour stage, lymph node metastasis, less favourable R category and worse overall patient survival. NRP2 up-regulation in ESCC was in part a result of gene amplification at chromosome 2q. NRP2 overexpression promoted clonogenicity, angiogenesis and metastasis in ESCC in vitro, while NRP2 silencing by lentiviral knockdown or neutralizing antibody resulted in a contrary effect. This observation was extended in vivo in animal models of subcutaneous tumourigenicity and tail vein metastasis. Mechanistically, overexpression of NRP2 induced expression of ERK MAP kinase and the transcription factor ETV4, leading to enhanced MMP-2 and MMP-9 activity and, as a consequence, suppression of E-cadherin. In summary, NRP2 promotes tumourigenesis and metastasis in ESCC through deregulation of ERK-MAPK-ETV4-MMP-E-cadherin signalling. NRP2 represents a potential diagnostic or prognostic biomarker and therapeutic target for ESCC. Copyright (C) 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.