From the College of Dental Medicine, Western University of Health Sciences, Pomona, CA 91766-1854 USA.
College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766-1854 USA.
Neoplasia. 2015 Jan;17(1):141-51. doi: 10.1016/j.neo.2014.12.002.
Epidermal growth factor receptor (EGFR) is overexpressed in head and neck squamous cell carcinoma (HNSCC) where it has been shown to promote tumor cell invasion upon phosphorylation. One mechanism by which EGFR promotes tumor progression is by activating signal cascades that lead to loss of E-cadherin, a transmembrane glycoprotein of the cell-cell adherence junctions; however mediators of these signaling cascades are not fully understood. One such mediator, RhoC, is activated upon a number of external stimuli, such as epidermal growth factor (EGF), but its role as a mediator of EGF-stimulated migration and invasion has not been elucidated in HNSCC. In the present study, we investigate the role of RhoC as a mediator of EGF-stimulated migration and invasion in HNSCC. We show that upon EGF stimulation, EGFR and RhoC were strongly activated in HNSCC. This resulted in activation of the phosphatidylinositol 3-Kinase Akt pathway (PI3K-Akt), phosphorylation of GSK-3β at the Ser(9) residue, and subsequent down regulation of E-cadherin cell surface expression resulting in increased tumor cell invasion. Knockdown of RhoC restored E-cadherin expression and inhibited EGF-stimulated migration and invasion. This is the first report in HNSCC demonstrating the role RhoC plays in mediating EGF-stimulated migration and invasion by down-regulating the PI3K-Akt pathway and E-cadherin expression. RhoC may serve as a treatment target for HNSCC.
表皮生长因子受体（EGFR）在头颈部鳞状细胞癌（HNSCC）中过度表达，已被证明在磷酸化后促进肿瘤细胞侵袭。EGFR 促进肿瘤进展的一种机制是通过激活信号级联反应，导致细胞-细胞黏附连接的跨膜糖蛋白 E-钙黏蛋白的丢失；然而，这些信号级联反应的介质尚未完全阐明。RhoC 是其中一种介质，它会被多种外部刺激物激活，如表皮生长因子（EGF），但其在 HNSCC 中作为 EGF 刺激的迁移和侵袭的介质的作用尚未阐明。在本研究中，我们研究了 RhoC 在 HNSCC 中作为 EGF 刺激的迁移和侵袭的介质的作用。我们发现，在 EGF 刺激下，EGFR 和 RhoC 在 HNSCC 中被强烈激活。这导致了磷脂酰肌醇 3-激酶 Akt 途径（PI3K-Akt）的激活、GSK-3β 在 Ser(9)残基上的磷酸化，以及随后 E-钙黏蛋白细胞表面表达的下调，导致肿瘤细胞侵袭增加。RhoC 的敲低恢复了 E-钙黏蛋白的表达，并抑制了 EGF 刺激的迁移和侵袭。这是 HNSCC 中首次报道 RhoC 通过下调 PI3K-Akt 途径和 E-钙黏蛋白表达来介导 EGF 刺激的迁移和侵袭的作用。RhoC 可能可作为 HNSCC 的治疗靶点。
