4.6 Review

PAG1 promotes the inherent radioresistance of laryngeal cancer cells via activation of STAT3

Journal

EXPERIMENTAL CELL RESEARCH
Volume 370, Issue 1, Pages 127-136

Publisher

ELSEVIER INC
DOI: 10.1016/j.yexcr.2018.06.014

Keywords

PAG1; Inherent radioresistance; STAT3; Laryngeal cancer

Funding

  1. National Natural Science Foundation of China [81502666, 81602391]
  2. Initial Project for Post-Graduates of Hubei University of Medicine [2016QDJZR10]
  3. Natural Science Foundation of Hubei Province [2015CFA076]

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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 beta 1 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.

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