title: Fibronectin promotes cell proliferation and invasion through mTOR signaling pathway activation in gallbladder cancer.
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.
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Yang
authors: Y
authors: Cao
authors: Department of Molecular Pharmacology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA.
authors: Xiyong
authors: X
authors: Liu
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Social Cognitive and Behavioral Sciences, Shanghai Jiao Tong University, Shanghai, China.
authors: Wei
authors: W
authors: Lu
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Yuanyuan
authors: Y
authors: Chen
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Xiangsong
authors: X
authors: Wu
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Maolan
authors: M
authors: Li
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Xu-An
authors: XA
authors: Wang
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Fei
authors: F
authors: Zhang
authors: Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Lin
authors: L
authors: Jiang
authors: Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Yijian
authors: Y
authors: Zhang
authors: Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Yunping
authors: Y
authors: Hu
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Shanshan
authors: S
authors: Xiang
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Yijun
authors: Y
authors: Shu
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Runfa
authors: R
authors: Bao
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Huaifeng
authors: H
authors: Li
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Wenguang
authors: W
authors: Wu
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Hao
authors: H
authors: Weng
authors: Department of Molecular Pharmacology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA. Electronic address: yyen@coh.org.
authors: Yun
authors: Y
authors: Yen
authors: Department of General Surgery, Xinhua Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; Institute of Biliary Tract Disease, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: liuybphd@126.com.
authors: Yingbin
authors: Y
authors: Liu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation / Q000502:physiology; D005260:Female; D005353:Fibronectins / Q000096:biosynthesis*; D005706:Gallbladder Neoplasms / Q000378:metabolism* / Q000473:pathology*; D064593:Heterografts; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000556:secondary; D008297:Male; D051379:Mice; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D005353:Fibronectins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases
keywords: Fibronectin; Gallbladder cancer; Invasion; Proliferation; mTOR