Fibrinogen promotes malignant biological tumor behavior involving epithelial–mesenchymal transition via the p-AKT/p-mTOR pathway in esophageal squamous cell carcinoma

Abstract

Purpose

Hyperfibrinogenemia is associated with unfavorable prognosis and advanced tumor behavior in various malignancies, including esophageal squamous cell carcinoma (ESCC). However, its biological function in ESCC is unknown. The present study was designed to further validate the prognostic value of preoperative plasma hyperfibrinogenemia and evaluate the biological role of fibrinogen, as well as the underlying mechanism in ESCC.

Methods

Data from 452 cases with newly diagnosed ESCC followed by curative surgery between 2006 and 2010 were retrospectively evaluated. The Clauss method was utilized to measure the preoperative plasma fibrinogen level. Correlations between the fibrinogen level and clinicopathologic characteristics and survival analysis were performed. The effects of fibrinogen on malignant behaviors, including tumor cell viability, colony formation, migration, and invasion, were also investigated.

Results

The optimal cut-off value for plasma fibrinogen level was defined as 4.0 g/L according to recommendations. Thus, the proportion of hyperfibrinogenemia was 24.8% (112/452). Preoperative plasma hyperfibrinogenemia was significantly associated with advanced tumor length, deep tumor invasion, advanced tumor–node–metastasis stage, alcohol consumption, a higher white blood cell count, a higher platelet count, and high globulin levels. Univariate survival analysis revealed that compared to those with normal plasma fibrinogen levels, patients with hyperfibrinogenemia tended to have poorer disease-free survival (DFS) [hazard ratio (HR), 1.692; 95% confidence interval (CI), 1.304–2.196; P < 0.001] and overall survival (OS) (HR 1.864; 95% CI 1.424–2.440; P < 0.001). In the multivariate Cox regression models, these factors remained independent predictors for impaired DFS (HR 1.491; 95% CI 1.138–1.955; P = 0.004) and OS (HR 1.648; 95% CI 1.246–2.180; P < 0.001) after adjusting for other confounding variables. In addition, fibrinogen could significantly promote cell migration and invasion but not proliferation. Moreover, it could also induce epithelial–mesenchymal transition (EMT) and increase the levels of p-PTEN, p-AKT, and p-mTOR in ESCC cell lines.

Conclusions

Preoperative plasma hyperfibrinogenemia might serve as an independent predictor of unfavorable survival in ESCC. Furthermore, fibrinogen may promote cell motility by inducing EMT via the p-AKT/p-mTOR pathway.

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