Division of Gastroenterology and Hepatology, Key Laboratory of Gastroenterology and Hepatology, Ministry of Health, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai Institute of Digestive Disease, Shanghai, 200001, China.
Department of Digestive Endoscopy, Provincial Clinic Medical College, Fujian Medical University, Fujian Provincial Hospital, Fuzhou, 350001, China.
Cell Mol Life Sci. 2020 Dec;77(24):5207-5221. doi: 10.1007/s00018-020-03465-3. Epub 2020 Feb 1.
Small bowel vascular malformation disease (SBVM) is the most common cause of obscure gastrointestinal bleeding (OGIB). Several studies suggested that EGFL6 was able to promote the growth of tumor endothelial cells by forming tumor vessels. To date, it remains unclear how EGFL6 promotes pathological angiogenesis in SBVM and whether EGFL6 is a target of thalidomide.
We took advantage of SBVM plasma and tissue samples and compared the expression of EGFL6 between SBVM patients and healthy people via ELISA and Immunohistochemistry. We elucidated the underlying function of EGFL6 in SBVM in vitro and by generating a zebrafish model that overexpresses EGFL6, The cycloheximide (CHX)-chase experiment and CoIP assays were conducted to demonstrate that thalidomide can promote the degradation of EGFL6 by targeting CRBN.
The analysis of SBVM plasma and tissue samples revealed that EGFL6 was overexpressed in the patients compared to healthy people. Using in vitro and in vivo assays, we demonstrated that an EMT pathway triggered by the EGFL6/PAX6 axis is involved in the pathogenesis of SBVM. Furthermore, through in vitro and in vivo assays, we elucidated that thalidomide can function as anti-angiogenesis medicine through the regulation of EGFL6 in a proteasome-dependent manner. Finally, we found that CRBN can mediate the effect of thalidomide on EGFL6 expression and that the CRBN protein interacts with EGFL6 via a Lon N-terminal peptide.
Our findings revealed a key role for EGFL6 in SBVM pathogenesis and provided a mechanism explaining why thalidomide can cure small bowel bleeding resulting from SBVM.
小肠血管畸形病（SBVM）是不明原因胃肠道出血（OGIB）的最常见原因。有几项研究表明，EGFL6 能够通过形成肿瘤血管来促进肿瘤内皮细胞的生长。迄今为止，尚不清楚 EGFL6 如何促进 SBVM 中的病理性血管生成，以及 EGFL6 是否是沙利度胺的靶点。
我们利用 SBVM 血浆和组织样本，通过 ELISA 和免疫组化比较了 SBVM 患者和健康人之间 EGFL6 的表达。我们在体外和斑马鱼模型中阐明了 EGFL6 在 SBVM 中的潜在功能，该模型通过过表达 EGFL6 生成。进行了环己酰亚胺（CHX）追踪实验和 CoIP 测定，以证明沙利度胺可以通过靶向 CRBN 促进 EGFL6 的降解。
对 SBVM 血浆和组织样本的分析表明，与健康人相比，EGFL6 在患者中过度表达。通过体外和体内试验，我们证明了 EGFL6/PAX6 轴触发的 EMT 途径参与了 SBVM 的发病机制。此外，通过体外和体内试验，我们阐明了沙利度胺可以通过调节 EGFL6 以依赖蛋白酶体的方式发挥抗血管生成药物的作用。最后，我们发现 CRBN 可以介导沙利度胺对 EGFL6 表达的影响，并且 CRBN 蛋白通过 Lon N 端肽与 EGFL6 相互作用。
我们的研究结果揭示了 EGFL6 在 SBVM 发病机制中的关键作用，并提供了一种解释为什么沙利度胺可以治愈由 SBVM 引起的小肠出血的机制。
