Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, PR China; Department of Biochemistry, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei 442000, PR China.
Department of Clinical Oncology, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, PR China.
Exp Cell Res. 2018 Sep 1;370(1):127-136. doi: 10.1016/j.yexcr.2018.06.014. Epub 2018 Jun 18.
Phosphoprotein associated with glycosphingolipid-enriched microdomains 1(PAG1) is a ubiquitous protein that is essential for the development and progression of various malignancies. A previous study in our laboratory confirmed that PAG1 plays an important role in modulating the inherent radioresistance of laryngeal cancer cells, but the underlying mechanisms are still poorly defined. In this study, we found that PAG1 was significantly increased in laryngeal cancer tissues compared to adjacent non-tumor tissues (P < 0.05). The expression of PAG1 was positively correlated with lymph node metastasis (P < 0.05) and TNM stage (P < 0.05). High expression of PAG1 also predicted a poor prognosis in patients with laryngeal cancer. Moreover, gain-of-function and loss-of-function studies showed that PAG1 overexpression was able to promote growth, increase migration and invasion, and enhance inherent radioresistance of laryngeal cancer cells. Mechanistic investigations revealed that the activation of STAT3 was required for PAG1-mediated inherent radioresistance of laryngeal cancer. Inhibition of STAT3 activity with a chemical inhibitor sensitized radioresistant cells to radiation. Importantly, PAG1-integrin β1 complex was involved in the regulation of STAT3 activation. In addition, downregulation of PAG1 could suppress tumor growth and reverse inherent radioresistance in the nude mouse xenograft model. Taken together, these results suggested that PAG1 conferred inherent radioresistance by activating STAT3, which provided a novel therapeutic strategy for laryngeal cancer.
糖脂富集微区相关磷蛋白 1（PAG1）是一种普遍存在的蛋白质，对于各种恶性肿瘤的发生和发展至关重要。我们实验室的先前研究证实，PAG1 在调节喉癌细胞固有放射抵抗性方面发挥着重要作用，但潜在机制仍未完全阐明。在本研究中，我们发现与相邻非肿瘤组织相比，PAG1 在喉癌组织中显著增加（P<0.05）。PAG1 的表达与淋巴结转移（P<0.05）和 TNM 分期（P<0.05）呈正相关。PAG1 的高表达也预示着喉癌患者预后不良。此外，功能获得和功能丧失研究表明，PAG1 的过表达能够促进生长、增加迁移和侵袭，并增强喉癌细胞的固有放射抵抗性。机制研究表明，STAT3 的激活是 PAG1 介导的喉癌细胞固有放射抵抗性所必需的。用化学抑制剂抑制 STAT3 活性可使耐辐射细胞对辐射敏感。重要的是，PAG1-整合素β1 复合物参与了 STAT3 激活的调节。此外，下调 PAG1 可抑制裸鼠异种移植模型中的肿瘤生长并逆转固有放射抵抗性。总之，这些结果表明 PAG1 通过激活 STAT3 赋予喉癌细胞固有放射抵抗性，为喉癌提供了一种新的治疗策略。
