Abstract：
BACKGROUND: Colorectal cancer (CRC) remains largely incurable when diagnosed at the metastatic stage. Despite some advances in precision medicine for this disease in recent years, new molecular targets, as well as prognostic/predictive markers, are highly needed. Neuroligin 1 (NLGN1) is a transmembrane protein that interacts at the synapse with the tumor suppressor adenomatous polyposis Coli (APC), which is heavily involved in the pathogenesis of CRC and is a key player in the WNT/β-catenin pathway.
METHODS: After performing expression studies of NLGN1 on human CRC samples, in this paper we used in vitro and in vivo approaches to study CRC cells extravasation and metastasis formation capabilities. At the molecular level, the functional link between APC and NLGN1 in the cancer context was studied.
RESULTS: Here we show that NLGN1 is expressed in human colorectal tumors, including clusters of aggressive migrating (budding) single tumor cells and vascular emboli. We found that NLGN1 promotes CRC cells crossing of an endothelial monolayer (i.e. Trans-Endothelial Migration or TEM) in vitro, as well as cell extravasation/lung invasion and differential organ metastatization in two mouse models. Mechanistically, NLGN1 promotes APC localization to the cell membrane and co-immunoprecipitates with some isoforms of this protein stimulates β-catenin translocation to the nucleus, upregulates mesenchymal markers and WNT target genes and induces an \"EMT phenotype\" in CRC cell lines CONCLUSIONS: In conclusion, we have uncovered a novel modulator of CRC aggressiveness which impacts on a critical pathogenetic pathway of this disease, and may represent a novel therapeutic target, with the added benefit of carrying over substantial knowledge from the neurobiology field.
METHODS: After performing expression studies of NLGN1 on human CRC samples, in this paper we used in vitro and in vivo approaches to study CRC cells extravasation and metastasis formation capabilities. At the molecular level, the functional link between APC and NLGN1 in the cancer context was studied.
RESULTS: Here we show that NLGN1 is expressed in human colorectal tumors, including clusters of aggressive migrating (budding) single tumor cells and vascular emboli. We found that NLGN1 promotes CRC cells crossing of an endothelial monolayer (i.e. Trans-Endothelial Migration or TEM) in vitro, as well as cell extravasation/lung invasion and differential organ metastatization in two mouse models. Mechanistically, NLGN1 promotes APC localization to the cell membrane and co-immunoprecipitates with some isoforms of this protein stimulates β-catenin translocation to the nucleus, upregulates mesenchymal markers and WNT target genes and induces an \"EMT phenotype\" in CRC cell lines CONCLUSIONS: In conclusion, we have uncovered a novel modulator of CRC aggressiveness which impacts on a critical pathogenetic pathway of this disease, and may represent a novel therapeutic target, with the added benefit of carrying over substantial knowledge from the neurobiology field.
摘要：
背景：在转移阶段诊断时，结直肠癌（CRC）在很大程度上仍然无法治愈。尽管近年来这种疾病的精准医学取得了一些进展，新的分子靶标，以及预后/预测标志物，是非常需要的。Neuroligin1（NLGN1）是一种跨膜蛋白，在突触处与肿瘤抑制腺瘤性息肉病（APC）相互作用，它与CRC的发病机制密切相关，并且是WNT/β-catenin通路的关键参与者。
方法：在对人类CRC样本进行NLGN1表达研究后，在本文中，我们使用体外和体内方法来研究CRC细胞的外渗和转移形成能力。在分子水平上,研究了APC和NLGN1在癌症中的功能联系.
结果：这里我们显示NLGN1在人类结直肠肿瘤中表达，包括侵袭性迁移（出芽）单个肿瘤细胞和血管栓塞的簇。我们发现NLGN1在体外促进CRC细胞穿过内皮单层（即跨内皮迁移或TEM），以及两种小鼠模型中的细胞外渗/肺侵袭和分化器官转移。机械上,NLGN1促进APC定位到细胞膜上，并与该蛋白的一些同工型共免疫沉淀刺激β-catenin易位到细胞核，上调间充质标志物和WNT靶基因，并在CRC细胞系中诱导“EMT表型”。我们发现了一种新的CRC侵袭性调节剂，它影响该疾病的关键致病途径，并可能代表一个新的治疗靶点，从神经生物学领域继承大量知识的额外好处。
方法：在对人类CRC样本进行NLGN1表达研究后，在本文中，我们使用体外和体内方法来研究CRC细胞的外渗和转移形成能力。在分子水平上,研究了APC和NLGN1在癌症中的功能联系.
结果：这里我们显示NLGN1在人类结直肠肿瘤中表达，包括侵袭性迁移（出芽）单个肿瘤细胞和血管栓塞的簇。我们发现NLGN1在体外促进CRC细胞穿过内皮单层（即跨内皮迁移或TEM），以及两种小鼠模型中的细胞外渗/肺侵袭和分化器官转移。机械上,NLGN1促进APC定位到细胞膜上，并与该蛋白的一些同工型共免疫沉淀刺激β-catenin易位到细胞核，上调间充质标志物和WNT靶基因，并在CRC细胞系中诱导“EMT表型”。我们发现了一种新的CRC侵袭性调节剂，它影响该疾病的关键致病途径，并可能代表一个新的治疗靶点，从神经生物学领域继承大量知识的额外好处。
