CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion.
CAR Co-Operates With Integrins to Promote Lung Cancer Cell Adhesion and Invasion.
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DOI：
10.3389/fonc.2022.829313
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发表时间：
2022
影响因子：
4.7
通讯作者：
Parsons M
中科院分区：
文献类型：
--
作者：
Owczarek C;Ortiz-Zapater E;Kim J;Papaevangelou E;Santis G;Parsons M
科萨基和腺病毒受体（CAR）是粘附受体的连接粘附分子（JAM）家族的成员，并且定位于上皮细胞紧密连接和粘附连接。CAR在肺癌中高度表达，被认为可以促进肿瘤生长和调节上皮间质转化（EMT），但CAR在肺癌转移中的潜在作用仍知之甚少。为了更好地理解这种受体在肿瘤进展中的作用，我们操纵了上皮样和间充质样肺癌细胞中的CAR表达。在这两种情况下，CAR过表达促进了免疫活性小鼠体内的肿瘤生长，并增加了静脉注射后肺中的细胞粘附，而不改变每种细胞系的EMT特性。WTCAR的过表达导致3D模型中的侵袭增加，并增强两种细胞系中的β1整联蛋白活性，这依赖于CAR胞质尾的磷酸化。此外，CAR的磷酸化在体外被底物硬度增强，并且CAR表达在体内实体瘤的边界处增加。此外，CAR与粘着斑蛋白Src、粘着斑激酶（FAK）和桩蛋白形成复合物，并促进三磷酸鸟嘌呤（GTP）-酶Ras相关蛋白1（Rap 1）的活化，其进而介导增强的整合素活化。总而言之，我们的数据表明CAR通过促进细胞与基质粘附而促进肺癌转移，为调节肿瘤发生不同步骤的细胞-细胞和细胞-基质蛋白之间的合作提供了新的见解。
The coxsackie and adenovirus receptor (CAR) is a member of the junctional adhesion molecule (JAM) family of adhesion receptors and is localised to epithelial cell tight and adherens junctions. CAR has been shown to be highly expressed in lung cancer where it is proposed to promote tumor growth and regulate epithelial mesenchymal transition (EMT), however the potential role of CAR in lung cancer metastasis remains poorly understood. To better understand the role of this receptor in tumor progression, we manipulated CAR expression in both epithelial-like and mesenchymal-like lung cancer cells. In both cases, CAR overexpression promoted tumor growth in vivo in immunocompetent mice and increased cell adhesion in the lung after intravenous injection without altering the EMT properties of each cell line. Overexpression of WTCAR resulted in increased invasion in 3D models and enhanced β1 integrin activity in both cell lines, and this was dependent on phosphorylation of the CAR cytoplasmic tail. Furthermore, phosphorylation of CAR was enhanced by substrate stiffness in vitro, and CAR expression increased at the boundary of solid tumors in vivo. Moreover, CAR formed a complex with the focal adhesion proteins Src, Focal Adhesion Kinase (FAK) and paxillin and promoted activation of the Guanine Triphosphate (GTP)-ase Ras-related Protein 1 (Rap1), which in turn mediated enhanced integrin activation. Taken together, our data demonstrate that CAR contributes to lung cancer metastasis via promotion of cell-matrix adhesion, providing new insight into co-operation between cell-cell and cell-matrix proteins that regulate different steps of tumorigenesis.
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影响因子：
11.5
作者：
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影响因子：
4
作者：
Asuri, Sirisha;Yan, Jingliang;Paranavitana, Nivanka C.;Quilliam, Lawrence A.
通讯作者：
Quilliam, Lawrence A.