Miller Julia, Dreyer Tobias F, Bächer Anne Sophie, Sinner Eva-Kathrin, Heinrich Christine, Benge Anke, Gross Eva, Preis Sarah, Rother Jan, Roberts Anthony, Nelles Gabriele, Miteva Tzenka, Reuning Ute
Department for Obstetrics & Gynecology, Technical University of Munich, D-81675 Munich, Germany.
BOKU, University of Natural Resources and Life Sciences, 1180 Vienna, Austria.
Oncotarget. 2018 Jan 5;9(5):6369-6390. doi: 10.18632/oncotarget.23968. eCollection 2018 Jan 19.
The tetraspanin and tumor suppressor KAI1 is downregulated or lost in many cancers which correlates with poor prognosis. KAI1 acts via physical/functional crosstalk with other membrane receptors. Also, a splice variant of KAI1 (KAI1-SP) has been identified indicative of poor prognosis. We here characterized differential effects of the two KAI1 variants on tumor biological events involving integrin (αvß3) and/or epidermal growth factor receptor (EGF-R). In MDA-MB-231 and -435 breast cancer cells, differential effects were documented on the expression levels of the tumor biologically relevant integrin αvß3 which colocalized with KAI1-WT but not with KAI1-SP. Cellular motility was assessed by video image processing, including motion detection and vector analysis for the quantification and visualization of cell motion parameters. In MDA-MB-231 cells, KAI1-SP provoked a quicker wound gap closure and higher closure rates than KAI1-WT, also reflected by different velocities and average motion amplitudes of singular cells. KAI1-SP induced highest cell motion adjacent to the wound gap borders, whereas in MDA-MB-435 cells a comparable induction of both KAI1 variants was noticed. Moreover, while KAI1-WT reduced cell growth, KAI1-SP significantly increased it going along with a pronounced EGF-R upregulation. KAI1-SP-induced cell migration and proliferation was accompanied by the activation of the focal adhesion and Src kinase. Our findings suggest that splicing of KAI1 does not only abrogate its tumor suppressive functions, but even more, promotes tumor biological effects in favor of cancer progression and metastasis.
四跨膜蛋白及肿瘤抑制因子KAI1在许多癌症中表达下调或缺失，这与预后不良相关。KAI1通过与其他膜受体的物理/功能相互作用发挥作用。此外，已鉴定出KAI1的一种剪接变体（KAI1-SP），其提示预后不良。我们在此表征了这两种KAI1变体对涉及整合素（αvβ3）和/或表皮生长因子受体（EGF-R）的肿瘤生物学事件的不同影响。在MDA-MB-231和-435乳腺癌细胞中，记录到对与KAI1-WT共定位但不与KAI1-SP共定位的肿瘤生物学相关整合素αvβ3表达水平的不同影响。通过视频图像处理评估细胞运动，包括运动检测和矢量分析，以量化和可视化细胞运动参数。在MDA-MB-231细胞中，KAI1-SP比KAI1-WT引起更快的伤口间隙闭合和更高的闭合率，单个细胞的不同速度和平均运动幅度也反映了这一点。KAI1-SP在伤口间隙边界附近诱导最高的细胞运动，而在MDA-MB-435细胞中，两种KAI1变体的诱导作用相当。此外，虽然KAI1-WT降低细胞生长，但KAI1-SP显著增加细胞生长，同时伴有EGF-R的明显上调。KAI1-SP诱导的细胞迁移和增殖伴随着粘着斑和Src激酶的激活。我们的研究结果表明，KAI1的剪接不仅消除了其肿瘤抑制功能，而且更促进了有利于癌症进展和转移的肿瘤生物学效应。
