Liersch-Löhn Britta, Slavova Nadia, Buhr Heinz J, Bennani-Baiti Idriss M
Department of Surgery, Sana Klinikum Lichtenberg Berlin, Berlin, Germany.
Department of General, Vascular and Thoracic Surgery, Charité Universitätsmedizin Berlin, Campus Benjamin Franklin, Berlin, Germany.
Int J Cancer. 2016 Mar 1;138(5):1220-31. doi: 10.1002/ijc.29865. Epub 2015 Oct 15.
Transmembrane tyrosine-kinase Ephrin receptors promote tumor progression and/or metastasis of several malignancies including leukemia, follicular lymphoma, glioma, malignant pleural mesothelioma, papillary thyroid carcinoma, sarcomas and ovarian, breast, bladder and non-small cell lung cancers. They also drive intestinal stem cell proliferation and positioning, control intestinal tissue boundaries and are involved in liver, pancreatic and colorectal cancers, indicating involvement in additional digestive system malignancies. We investigated the role of Ephrin-B4 receptor (EPHB4), and its ligand EFNB2, in gastric and gastroesophageal junction cancers in patient cohorts through computational, mathematical, molecular and immunohistochemical analyses. We show that EPHB4 is upregulated in preneoplastic gastroesophageal lesions and its expression further increased in gastroesophageal cancers in several independent cohorts. The closely related EPHB6 receptor, which also binds EFNB2, was downregulated in all tested cohorts, consistent with its tumor-suppressive properties in other cancers. EFNB2 expression is induced in esophageal cells by acidity, suggesting that gastroesophageal reflux disease (GERD) may constitute an early triggering event in activating EFNB2-EPHB4 signaling. Association of EPHB4 to both Barrett's esophagus and to advanced tumor stages, and its overexpression at the tumor invasion front and vascular endothelial cells intimate the notion that EPHB4 may be associated with multiple steps of gastroesophageal tumorigenesis. Analysis of oncogenomic signatures uncovered the first EPHB4-associated gene network (false discovery rate: 7 × 10(-90) ) composed of a five-transcription factor interconnected gene network that drives proliferation, angiogenesis and invasiveness. The EPHB4 oncogenomic network provides a molecular basis for its role in tumor progression and points to EPHB4 as a potential tumor aggressiveness biomarker and drug target in gastroesophageal cancers.
跨膜酪氨酸激酶 Ephrin 受体促进多种恶性肿瘤的进展和/或转移，包括白血病、滤泡性淋巴瘤、神经胶质瘤、恶性胸膜间皮瘤、甲状腺乳头状癌、肉瘤以及卵巢癌、乳腺癌、膀胱癌和非小细胞肺癌。它们还驱动肠道干细胞增殖和定位，控制肠道组织边界，并参与肝癌、胰腺癌和结直肠癌，表明其参与了其他消化系统恶性肿瘤。我们通过计算、数学、分子和免疫组化分析，研究了 Ephrin-B4 受体（EPHB4）及其配体 EFNB2 在患者队列的胃癌和胃食管交界癌中的作用。我们发现，在几个独立队列中，EPHB4 在癌前胃食管病变中上调，其表达在胃食管癌中进一步增加。同样与 EFNB2 结合的密切相关的 EPHB6 受体在所有测试队列中均下调，这与其在其他癌症中的肿瘤抑制特性一致。酸性物质可诱导食管细胞中 EFNB2 的表达，这表明胃食管反流病（GERD）可能是激活 EFNB2-EPHB4 信号的早期触发事件。EPHB4 与巴雷特食管和晚期肿瘤阶段均相关，并且在肿瘤侵袭前沿和血管内皮细胞中过度表达，这暗示 EPHB4 可能与胃食管肿瘤发生的多个步骤相关。对肿瘤基因组特征的分析揭示了第一个与 EPHB4 相关的基因网络（错误发现率：7×10⁻⁹⁰），该网络由一个驱动增殖、血管生成和侵袭的五转录因子相互连接的基因网络组成。EPHB4 肿瘤基因组网络为其在肿瘤进展中的作用提供了分子基础，并指出 EPHB4 是胃食管癌中潜在的肿瘤侵袭性生物标志物和药物靶点。
