Role of LPAR3, PKC and EGFR in LPA-induced cell migration in oral squamous carcinoma cells.
Role of LPAR3, PKC and EGFR in LPA-induced cell migration in oral squamous carcinoma cells.
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DOI：
10.1186/1471-2407-14-432
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发表时间：
2014-06-13
期刊：
影响因子：
3.8
通讯作者：
Christoffersen T
中科院分区：
文献类型：
--
作者：
Brusevold IJ;Tveteraas IH;Aasrum M;Ødegård J;Sandnes DL;Christoffersen T
口腔鳞状细胞癌是一种侵袭性肿瘤，发病率和死亡率高，其典型的传播方式是局部浸润性生长。溶血磷脂酸（LPA）参与许多生物学过程，并可能在癌细胞迁移和侵袭中发挥作用。LPA存在于大多数组织中，可以通过六种不同的LPA受体（LPAR 1 -6）激活细胞。尽管LPA主要是促迁移的，但某些受体在某些细胞中可能具有抗迁移作用。LPA的信号传导机制尚未完全了解，在口腔癌细胞中，参与LPA刺激迁移的特异性受体和途径尚不清楚。研究了口腔癌细胞系E10、SCC-9和D2。在划痕试验中研究了细胞迁移，并在器官型三维共培养中证明了侵袭。用Western blotting和qRT-PCR研究LPA受体的蛋白和mRNA表达。用Western印迹和等电聚焦检查信号蛋白的激活，并使用针对特定受体和途径的药理学试剂和siRNA进一步探索信号传导机制。LPA刺激两种口腔癌细胞系E10和SCC-9的细胞迁移，但在D2中略有抑制。受体表达谱和特异性药理学拮抗剂和激动剂的作用表明，在E10和SCC-9中，LPA刺激的细胞迁移是通过LPAR 3介导的。此外，在这两种细胞系中，LPA的刺激依赖于PKC活性。然而，虽然LPA诱导EGFR的反式激活和刺激的迁移被阻断的EGFR抑制剂在E10细胞，LPA不诱导EGFR的反式激活在SCC-9细胞。在D2细胞中，LPA诱导EGFR反式激活，但这与这些细胞中非常高的固有迁移率的减慢有关。结果表明，LPA刺激的迁移在口腔癌细胞通过LPAR 3，进一步介导的PKC，其作用与EGFR反式激活一致或独立。
Oral squamous cell carcinoma is an aggressive neoplasm with serious morbidity and mortality, which typically spreads through local invasive growth. Lysophosphatidic acid (LPA) is involved in a number of biological processes, and may have a role in cancer cell migration and invasiveness. LPA is present in most tissues and can activate cells through six different LPA receptors (LPAR1-6). Although LPA is predominantly promigratory, some of the receptors may have antimigratory effects in certain cells. The signalling mechanisms of LPA are not fully understood, and in oral carcinoma cells the specific receptors and pathways involved in LPA-stimulated migration are unknown. The oral carcinoma cell lines E10, SCC-9, and D2 were investigated. Cell migration was studied in a scratch wound assay, and invasion was demonstrated in organotypic three dimensional co-cultures. Protein and mRNA expression of LPA receptors was studied with Western blotting and qRT-PCR. Activation of signalling proteins was examined with Western blotting and isoelectric focusing, and signalling mechanisms were further explored using pharmacological agents and siRNA directed at specific receptors and pathways. LPA stimulated cell migration in the two oral carcinoma cell lines E10 and SCC-9, but was slightly inhibitory in D2. The receptor expression profile and the effects of specific pharmacological antagonist and agonists indicated that LPA-stimulated cell migration was mediated through LPAR3 in E10 and SCC-9. Furthermore, in both these cell lines, the stimulation by LPA was dependent on PKC activity. However, while LPA induced transactivation of EGFR and the stimulated migration was blocked by EGFR inhibitors in E10 cells, LPA did not induce EGFR transactivation in SCC-9 cells. In D2 cells, LPA induced EGFR transactivation, but this was associated with slowing of a very high inherent migration rate in these cells. The results demonstrate LPA-stimulated migration in oral carcinoma cells through LPAR3, mediated further by PKC, which acts either in concert with or independently of EGFR transactivation.
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