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

  • Original Article – Cancer Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

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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Author notes

  1. Fei Zhang, Yun Wang, and Peng Sun have contributed equally to this work.

Authors and Affiliations

  1. Collaborative Innovation Center for Cancer Medicine, Guangzhou, 510060, Guangdong, People’s Republic of China

    Fei Zhang, Yun Wang, Peng Sun, Zhi-qiang Wang, De-shen Wang, Dong-sheng Zhang, Feng-hua Wang, Jian-hua Fu, Rui-hua Xu & Yu-hong Li

  2. State Key Laboratory of Oncology in South China, Guangzhou, 510060, Guangdong, People’s Republic of China

    Fei Zhang, Yun Wang, Peng Sun, Zhi-qiang Wang, De-shen Wang, Dong-sheng Zhang, Feng-hua Wang, Jian-hua Fu, Rui-hua Xu & Yu-hong Li

  3. Department of Medical Oncology, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, People’s Republic of China

    Fei Zhang, Yun Wang, Peng Sun, Zhi-qiang Wang, De-shen Wang, Dong-sheng Zhang, Feng-hua Wang, Rui-hua Xu & Yu-hong Li

  4. Guangdong Esophageal Cancer Institute, Guangzhou, 510060, Guangdong, People’s Republic of China

    Jian-hua Fu

  5. Department of Thoracic Surgery, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, Guangzhou, 510060, Guangdong, People’s Republic of China

    Jian-hua Fu

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  1. Fei Zhang
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  2. Yun Wang
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  3. Peng Sun
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Correspondence to Yu-hong Li.

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432_2017_2493_MOESM1_ESM.tif

Fibrinogen demonstrates no effect on the proliferation or colony-formation ability of ESCC cells. (A) The viability of HKESC (left panel) and Eca109 (right panel) exposed to fibrinogen (72 h) was detected with an MTT assay. (B) The viability of the indicated cells treated with fibrinogen (0, 50, 200, and 400 μg/ml) at the indicated timepoints. (C) Images (left panel) and quantification (right panel) of colony formation of the indicated cells cultured with fibrinogen at different concentrations for 14 days (TIFF 3019 kb)

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Zhang, F., Wang, Y., Sun, P. et al. Fibrinogen promotes malignant biological tumor behavior involving epithelial–mesenchymal transition via the p-AKT/p-mTOR pathway in esophageal squamous cell carcinoma. J Cancer Res Clin Oncol 143, 2413–2424 (2017). https://doi.org/10.1007/s00432-017-2493-4

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  • DOI: https://doi.org/10.1007/s00432-017-2493-4

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