The Expression and Prognostic Impact of the PI3K/AKT/mTOR Signaling Pathway in Advanced Esophageal Squamous Cell Carcinoma

摘要

The abnormal phosphatase and tensin homolog expression and activated phosphoinositide-3 kinase/Protein kinase B (AKT)/mammalian target of rapamycin signaling pathway are involved in the progression of esophageal squamous cell carcinoma. By assessing the expression pattern of key components in the phosphoinositide-3 kinase/AKT/mammalian target of rapamycin signaling pathway by immunohistochemistry in tumor and nontumor esophageal mucosa from patients with esophageal squamous cell carcinomas, we aimed to carefully explore the relationship between the various protein expressions and clinicopathological factors, as well as patient outcome. A total of 145 tumor and 145 nontumor samples from patients with esophageal squamous cell carcinoma, collected from HuaShan Hospital (Shanghai, China) were evaluated. Clinical characteristics, the targeted protein expressions (including phosphatase and tensin homolog, phosphoinositide-3 kinase, AKT, p-AKT, mammalian target of rapamycin, p-mTOR, p70S6 kinase 1, p-P70S6K1, elongation initiation factor 4E binding protein-1, and p-4E-BP1, and survival rate were analyzed. Among them, phosphoinositide-3 kinase, AKT, p-AKT, mammalian target of rapamycin, p-mTOR, elongation initiation factor 4E binding protein-1, p70S6 kinase 1, and p-P70S6K1 proteins were significantly upregulated in tumor tissue. Conversely, phosphatase and tensin homolog was largely downregulated in tumor tissue, notably in pT3-T4 tumors. Low expression of phosphatase and tensin homolog whereas high expression of mammalian target of rapamycin signaling components in tumors was closely related to the presence of lymph node metastases and advanced TNM stage (all P < .05). Moreover phosphatase and tensin homolog, mammalian target of rapamycin, and p70S6 kinase 1 were correlated with overall survival as well as p-mTOR was correlated with progression-free survival (all P < .05). Overexpression of mammalian target of rapamycin was proved to be an independent adverse prognostic factor for overall survival in esophageal squamous cell carcinomas. Our results suggest that the phosphoinositide-3 kinase/AKT/mammalian target of rapamycin signaling pathway is activated in esophageal squamous cell carcinoma, with the low expression of phosphatase and tensin homolog and the high expression of the mammalian target of rapamycin component proteins (both total and phosphorylated) in tumor tissue. Our result might offer a new strategy for specific targeted therapy and prognostic assessment in esophageal cancer.