Fibronectin promotes cell proliferation and invasion through mTOR signaling pathway activation in gallbladder cancer

Yang Cao, Xiyong Liu, Wei Lu, Yuanyuan Chen, Xiangsong Wu, Maolan Li, Xu an Wang, Fei Zhang, Lin Jiang, Yijian Zhang, Yunping Hu, Shanshan Xiang, Yijun Shu, Runfa Bao, Huaifeng Li, Wenguang Wu, Hao Weng, Yun Yen, Yingbin Liu

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37 Citations (Scopus)

Abstract

Fibronectin (FN), a heterodimeric glycoprotein overexpressed in several types of tumors, has been implicated in cancer progression via the activation of integrin-mediated pro-oncogenic pathways. The FN level in human bile fluid is dramatically increased in malignant biliary diseases; however, FN expression and its biological functions in gallbladder cancer (GBC) remain unknown. In this study, we found that FN was overexpressed in GBC tissues and was associated with a worse prognosis in GBC patients. In vitro experimental studies indicated that exogenous FN significantly enhanced cell proliferation, invasion and active MMP-9 secretion in human GBC cell lines (GBC-SD and NOZ). Moreover, the key kinases of the mTOR signaling pathway, including FAK, Akt, mTOR and 4E-BP1, were markedly activated in a time-dependent manner in FN-treated GBC-SD and NOZ cells. The IHC statistical analyses validated that FN expression was positively correlated with the phosphorylation levels of the 4E-BP1 protein in GBC tissues. Furthermore, rapamycin, a specific inhibitor of mTOR, almost completely blocked FN-induced phosphorylation of 4E-BP1 and also partially abrogated the stimulatory effects of FN on GBC cell proliferation and invasion. In vivo, FN treatment significantly promoted the proliferation and metastasis of GBC cells and markedly activated Akt/mTOR/4E-BP1 signaling cascade. These findings demonstrate that FN may play a critical role in the modulation of cell proliferation and invasion via mTOR signaling pathway activation during GBC progression.

Original languageEnglish
Pages (from-to)141-150
Number of pages10
JournalCancer Letters
Volume360
Issue number2
DOIs
Publication statusPublished - May 1 2015
Externally publishedYes

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Keywords

  • Fibronectin
  • Gallbladder cancer
  • Invasion
  • MTOR
  • Proliferation

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Cao, Y., Liu, X., Lu, W., Chen, Y., Wu, X., Li, M., Wang, X. A., Zhang, F., Jiang, L., Zhang, Y., Hu, Y., Xiang, S., Shu, Y., Bao, R., Li, H., Wu, W., Weng, H., Yen, Y., & Liu, Y. (2015). Fibronectin promotes cell proliferation and invasion through mTOR signaling pathway activation in gallbladder cancer. Cancer Letters, 360(2), 141-150. https://doi.org/10.1016/j.canlet.2015.01.041