Phosphorylation of Focal Adhesion Kinase at Tyr397 in Gastric Carcinomas and its Clinical Significance
Phosphorylation of Focal Adhesion Kinase at Tyr397 in Gastric Carcinomas and its Clinical Significance
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DOI：
10.2353/ajpath.2010.100172
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发表时间：
2010-10-01
影响因子：
6
通讯作者：
Shen, Tang-Long
中科院分区：
文献类型：
--
作者：
Lai, I-Rue;Chu, Pei-Yu;Shen, Tang-Long
粘着斑激酶(FAK)与多种肿瘤的发生有关，但目前尚不清楚FAK在体内如何参与肿瘤的恶性转化。本研究试图了解FAK激活在胃癌进展中的作用。应用免疫组织化学染色和Western blotting方法，我们发现59例胃癌组织中有21例表达FAK自身磷酸化位点pY397FAK。我们试图将临床病理参数，包括组织学类型、TNM分期和癌症复发与癌组织中FAK和pY397FAK的表达相关联。有趣的是，pY397FAK水平较高的患者显示出更高的胃癌术后复发率和较差的5年无复发生存率。此外，多因素分析显示pY397FAK是胃癌复发的独立预测因子。因此，pY397FAK的表达是影响胃癌复发的重要预后因素。此外，体外研究表明，与野生型FAK的过度表达相比，在AGS人胃癌细胞中过表达FAK的显性-负性突变体Y397F会损害细胞的迁移、侵袭和增殖。因此，FAK在Tyr397通过自身磷酸化激活，通过促进细胞迁移、侵袭和增殖而导致胃癌的进展。总而言之，我们的结果为胃癌治疗的新诊断和治疗靶点的开发提供了有价值的见解。(Am J Pathol2010,177：1629-1637；DOI：10.2353/ajpath.2010.100172)
Focal adhesion kinase (FAK) has been implicated in tumorigenesis in various cancers; however, it remains unclear how FAK participates in tumor malignancy in vivo. This study seeks to understand the role of FAK activation in gastric cancer progression. Using immunohistochemical staining and Western blotting, we found that pY397 FAK, an autophosphorylation site on FAK activation, was abundant in the cancerous tissues of 21 of 59 patients with gastric carcinomas. We attempted to correlate clinicopathological parameters, including histological types, TNM staging, and cancer recurrence, with the expression of FAK and pY397 FAK in cancerous tissues. Intriguingly, patients with higher levels of pY397 FAK displayed higher incidences of gastric cancer recurrence after surgery and poor 5-year recurrence-free survival. Furthermore, multivariate analyses showed that pY397 FAK was an independent predictor of gastric cancer recurrence. As a result, expression of pY397 FAK is a significant prognostic factor for the recurrence of gastric cancer. Additionally, in vitro studies showed that overexpression of Y397F, a dominant-negative mutant of FAK, in AGS human gastric carcinoma cells impaired cell migration, invasion, and proliferation compared with cells overexpressing wild-type FAK. Thus, activation of FAK through autophosphorylalion at Tyr397 leads to the progression of gastric carcinomas by promoting cell migration, invasion, and proliferation. Collectively, our results have provided valuable insights for the development of novel diagnoses and therapeutic targets for gastric cancer treatments. (Am J Pathol 2010, 177:1629-1637; DOI: 10.2353/ajpath.2010.100172)