The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/β-catenin pathway.
The neuronal protein Neuroligin 1 promotes colorectal cancer progression by modulating the APC/β-catenin pathway.
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DOI：
10.1186/s13046-022-02465-4
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发表时间：
2022-09-02
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影响因子：
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结直肠癌（CRC）在转移阶段诊断时，在很大程度上仍然无法治愈。尽管近年来在针对这种疾病的精准医学方面取得了一些进展，但仍然非常需要新的分子靶点以及预后/预测标记物。神经连接素1（NLGN 1）是一种跨膜蛋白，其在突触处与肿瘤抑制剂腺瘤性息肉病大肠杆菌（APC）相互作用，APC严重参与CRC的发病机制，并且是WNT/β-连环蛋白途径中的关键参与者。在对人结直肠癌标本进行NLGN 1表达研究后，本文采用体外和体内方法研究结直肠癌细胞的外渗和转移形成能力。在分子水平上，研究了APC和NLGN 1在癌症背景下的功能联系。在这里，我们发现NLGN 1在人类结直肠肿瘤中表达，包括侵袭性迁移（出芽）的单个肿瘤细胞和血管栓塞。我们发现NLGN 1在体外促进CRC细胞穿过内皮单层（即跨内皮迁移或TEM），以及在两种小鼠模型中促进细胞外渗/肺侵袭和分化器官转移。从机制上讲，NLGN 1促进APC定位于细胞膜，并与该蛋白的一些同种型共免疫沉淀，刺激β-连环蛋白易位至细胞核，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”。总之，我们已经发现了CRC侵袭性的新调节剂，其影响该疾病的关键致病途径，并且可以代表一种新的治疗靶点，具有继承神经生物学领域的大量知识的额外益处。在线版本包含补充材料，可通过10.1186/s13046-022-02465-4获得。
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. 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. 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 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. The online version contains supplementary material available at 10.1186/s13046-022-02465-4.
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影响因子：
7.3
作者：
Gao J;Aksoy BA;Dogrusoz U;Dresdner G;Gross B;Sumer SO;Sun Y;Jacobsen A;Sinha R;Larsson E;Cerami E;Sander C;Schultz N
通讯作者：
Schultz N
影响因子：
19
作者：
Bakir B;Chiarella AM;Pitarresi JR;Rustgi AK
通讯作者：
Rustgi AK
影响因子：
11.8
作者：
Krishnamurthy N;Kurzrock R
通讯作者：
Kurzrock R
DOI：
10.1073/pnas.0809510106
发表时间：
2009-12-08
影响因子：
11.1
作者：
Bottos, Alessia;Destro, Erika;Arese, Marco
通讯作者：
Arese, Marco
影响因子：
3.7
作者：
Xue Y;Li L;Zhang D;Wu K;Chen Y;Zeng J;Wang X;He D
通讯作者：
He D