Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells
Tyrosine 397 phosphorylation is critical for FAK-promoted Rac1 activation and invasive properties in oral squamous cell carcinoma cells
复制标题
DOI：
10.1038/labinvest.2015.151
复制
发表时间：
2016-03-01
影响因子：
5
通讯作者：
Yuan, Ta-Chun
中科院分区：
文献类型：
--
作者：
Chiu, Ya-Wen;Liou, Li-Yin;Yuan, Ta-Chun
口腔鳞状细胞癌（Oral squamous cell carcinoma，OSCC）是一种常见的恶性肿瘤。尽管在诊断和治疗方面取得了进展，但转移性OSCC患者的治疗选择很少，部分原因是对OSCC侵袭和转移所涉及的分子事件的了解有限。在这项研究中，我们研究了黏着斑激酶（FAK）及其酪氨酸397磷酸化（pY 397）在口腔鳞癌组织标本中的表达。进一步研究了pY 397对Rac 1和core-trin活性的调节作用以及对口腔鳞癌细胞侵袭性的影响。对9例良性、19例癌前病变和19例恶性口腔组织的免疫组化分析结果表明，FAK在5例良性组织（56%）、19例癌前病变（100%）和18例恶性组织（95%）中呈免疫阳性反应。而pY 397仅在9例良性病变中1例（11%）表达，在9例癌前病变（47%）和12例恶性病变（63%）表达。与低侵袭性SCC 4细胞相比，高侵袭性OECM-1细胞表现出更高水平的FAK表达和pY 397，与更高水平的GTP结合的Rac 1和corpine磷酸化相关。在SCC 4、FaDu、OECM-1或HSC-3细胞中操纵FAK表达或Y397磷酸化调节其Rac 1活性和侵袭特性。此外，在OECM-1和HSC-3细胞中，Rac 1特异性抑制剂NSC 23766的处理导致侵袭性降低。然而，敲低FAK表达或抑制pY 397对OECM-1细胞中的coronin活性没有影响。这些数据共同表明，pY 397在FAK促进的Rac 1激活和OSCC细胞的侵袭性中起着关键作用。因此，抑制FAK磷酸化Y397或Rac 1活性可以作为治疗转移性OSCC患者的治疗策略。
Oral squamous cell carcinoma (OSCC) is a common cancer worldwide. Despite advances in diagnosis and therapy, treatment options for patients with metastatic OSCC are few, due in part to the limited understanding of the molecular events involved in the invasion and metastasis of OSCC. In this study, we investigated the expression of focal adhesion kinase (FAK) and its tyrosine 397 phosphorylation (pY397) in the tissue specimens of OSCC. The roles of pY397 in regulating the activities of Rac1 and cortactin and the invasive properties of OSCC cells were further determined. Results from immunohistochemical analyses in 9 benign, 19 premalignant, and 19 malignant oral tissues showed that the immunoreactivity of FAK was observed in 5 benign (56%), 19 premalignant (100%), and 18 malignant tissues (95%), whereas the immunoreactivity of pY397 was only found in 1 of 9 (11%) benign lesions but was observed in 9 premalignant (47%) and 12 malignant (63%) lesions. Compared with the low-invading SCC4 cells, the high-invading OECM-1 cells exhibited higher levels of FAK expression and pY397, correlating with higher levels of GTP-bound Rac1 and cortactin phosphorylation. Manipulation of FAK expression or Y397 phosphorylation in SCC4, FaDu, OECM-1, or HSC-3 cells regulated their Rac1 activities and invasive properties. Furthermore, treatment of NSC23766, a Rac1-specific inhibitor, in OECM-1 and HSC-3 cells led to reduced invasive properties. Nevertheless, knockdown of FAK expression or suppression of pY397 had no effect on the cortactin activity in OECM-1 cells. The data collectively suggest that pY397 plays critical roles in the FAK-promoted Rac1 activation and invasive properties in OSCC cells. Thus, the inhibition of FAK phosphorylation at Y397 or Rac1 activity can serve as a therapeutic strategy for treating patients with metastatic OSCC.