PDF(Pubmed)
Abstract：
Lymph node metastasis, primarily caused by the migration of oral squamous cell carcinoma (OSCC) cells, stands as a crucial prognostic marker. We have previously demonstrated that EP4, a subtype of the prostaglandin E2 (PGE2) receptor, orchestrates OSCC cell migration via Ca2+ signaling. The exact mechanisms by which EP4 influences cell migration through Ca2+ signaling, however, is unclear. Our study aims to clarify how EP4 controls OSCC cell migration through this pathway. We find that activating EP4 with an agonist (ONO-AE1-473) increased intracellular Ca2+ levels and the migration of human oral cancer cells (HSC-3), but not human gingival fibroblasts (HGnF). Further RNA sequencing linked EP4 to calmodulin-like protein 6 (CALML6), whose role remains undefined in OSCC. Through protein-protein interaction network analysis, a strong connection is identified between CALML6 and calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), with EP4 activation also boosting mitochondrial function. Overexpressing EP4 in HSC-3 cells increases experimental lung metastasis in mice, whereas inhibiting CaMKK2 with STO-609 markedly lowers these metastases. This positions CaMKK2 as a potential new target for treating OSCC metastasis. Our findings highlight CALML6 as a pivotal regulator in EP4-driven mitochondrial respiration, affecting cell migration and metastasis via the CaMKK2 pathway.
摘要：
淋巴结转移,主要由口腔鳞状细胞癌（OSCC）细胞的迁移引起，作为一个关键的预后标志。我们以前已经证明，EP4，前列腺素E2（PGE2）受体的亚型，通过Ca2+信号协调OSCC细胞迁移。EP4通过Ca2+信号传导影响细胞迁移的确切机制，然而,不清楚。我们的研究旨在阐明EP4如何通过该途径控制OSCC细胞迁移。我们发现用激动剂（ONO-AE1-473）激活EP4可增加细胞内Ca2水平和人口腔癌细胞（HSC-3）的迁移，但不是人牙龈成纤维细胞（HGnF）。进一步的RNA测序将EP4与钙调蛋白样蛋白6（CALML6）连接，其角色在OSCC中仍未定义。通过蛋白质-蛋白质相互作用网络分析，CALML6和钙/钙调蛋白依赖性蛋白激酶激酶2（CaMKK2）之间有很强的联系，EP4激活也促进线粒体功能。在HSC-3细胞中过度表达EP4会增加小鼠的实验性肺转移，而用STO-609抑制CaMKK2可显着降低这些转移。这将CaMKK2定位为治疗OSCC转移的潜在新靶标。我们的发现强调CALML6是EP4驱动的线粒体呼吸的关键调节因子，通过CaMKK2途径影响细胞迁移和转移。
