Abstract：
Lymph nodes metastases are common in patients with lung cancer. Additionally, those patients are often at a higher risk for death from lung tumor than those with tumor-free lymph nodes. Somatic DNA alterations are key drivers of cancer, and copy number alterations (CNAs) are major types of DNA alteration that promote lung cancer progression. Here, we performed genome-wide DNA copy number analysis, and identified a novel lung-cancer-metastasis-related gene, EFNA4. The EFNA4 genome locus was significantly amplified, and EFNA4 mRNA expression was significantly up-regulated in lung cancer compared with normal lung tissue, and also in lung cancer with lymph node metastases compared with lung cancer without metastasis. EFNA4 encodes Ephrin A4, which is the ligand for Eph receptors. The function of EFNA4 in human lung cancer remains largely unknown. Through cell line experiments we showed that EFNA4 overexpression contributes to lung tumor cells growth, migration and adhesion. Conversely, EFNA4 knockdown or knockout led to the growth suppression of cells and tumor xenografts in mice. Lung cancer patients with EFNA4 overexpression have poor prognosis. Together, by elucidating a new layer of the role of EFNA4 in tumor proliferation and migration, our study demonstrates a better understanding of the function of the significantly amplified and overexpressed gene EFNA4 in lung tumor metastasis, and suggests EFNA4 as a potential target in metastatic lung cancer therapy.
摘要：
淋巴结转移在肺癌患者中很常见。此外,与无肿瘤淋巴结的患者相比,这些患者死于肺部肿瘤的风险通常更高.体细胞DNA改变是癌症的关键驱动因素，拷贝数改变（CNAs）是促进肺癌进展的主要DNA改变类型。这里,我们进行了全基因组DNA拷贝数分析,并鉴定出一种新的肺癌转移相关基因，EFNA4.EFNA4基因组位点显著扩增，与正常肺组织相比，肺癌中EFNA4mRNA表达明显上调，并且在有淋巴结转移的肺癌中也与无转移的肺癌相比。EFNA4编码EphrinA4，它是Eph受体的配体。EFNA4在人类肺癌中的功能仍然未知。通过细胞系实验我们发现EFNA4过表达有助于肺肿瘤细胞的生长,迁移和粘附。相反，EFNA4敲低或敲除导致小鼠中细胞和肿瘤异种移植物的生长抑制。EFNA4过表达的肺癌患者预后不良。一起,通过阐明EFNA4在肿瘤增殖和迁移中的新作用，我们的研究表明更好地理解显著扩增和过表达的基因EFNA4在肺肿瘤转移中的功能，并提示EFNA4是转移性肺癌治疗的潜在靶点。
