title: Fbxw7 regulates hepatocellular carcinoma migration and invasion via Notch1 signaling pathway.
abstract: Hepatocellular carcinoma (HCC) is one of the most common human malignancies and also the leading cause of cancer-related death in the world. The mechanisms underlying the progression and metastasis of HCC remain unclear. The E3 ubiquitin ligase F-box and WD repeat domain-containing 7 (Fbxw7) is broadly considered as a tumor suppressor gene. However, the role of Fbxw7 in HCC is not clear. To investigate the expression and biological functions of Fbxw7 in HCC, we examined Fbxw7 expression level using HCC tissue microarray and immunohistochemistry. Our data showed that Fbxw7 expression is significantly reduced in HCC compared with non-cancerous tissues (P<0.05). Fbxw7 levels were significantly associated with tumor differentiation (P=0.013), the incidence of portal or hepatic venous invasion (P=0.031), metastasis (P=0.027) and AJCC cancer stage (P=0.047). Then, we observed a strong correlation between low Fbxw7 expression and a worse 5-year survival of HCC patients (P<0.001). Furthermore, multivariate Cox regression analyses demonstrated that the Fbxw7 expression (P<0.001) was an independent factor for the prediction of the overall survival of HCC patients. We also found that both Fbxw7 mRNA and protein levels were significantly reduced in HCC cell lines compared with human liver non-tumor cell line. Moreover, our in vitro experiments showed a remarkable increase of cell migration and invasion in Fbxw7-knockdown cells and a decrease in Fbxw7-overexpress cells. In addition, the present study demonstrated that Fbxw7 is involved in the migration and invasion of HCC cells via regulating Notch1 and the downstream molecules of Notch1. Taken together, our findings indicate that Fbxw7 can be used as a prognostic marker; it has an important role in HCC progression and inhibits HCC cell migration and invasion through the Notch1 signaling pathway.
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China.
authors.forename: Xing
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of ENT, The 44 Central Hospital of PLA, Guiyang, Guizhou 550009, P.R. China.
authors.forename: Juan
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of General Surgery, The 155 Central Hospital of PLA, Kaifeng, Henan 471000, P.R. China.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhou
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China.
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Zheng
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China.
authors.forename: Peng
authors.initials: P
authors.lastname: Lu
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China.
authors.forename: Xi-Sheng
authors.initials: XS
authors.lastname: Yang
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China.
authors.forename: Zhuo-Chao
authors.initials: ZC
authors.lastname: Zhang
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China.
authors.forename: Kai-Shan
authors.initials: KS
authors.lastname: Tao
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, The Fourth Military Medical University, Xi'an, Shannxi 710032, P.R. China.
authors.forename: Ke-Feng
authors.initials: KF
authors.lastname: Dou
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement; D044783:F-Box Proteins / Q000235:genetics* / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D044767:Ubiquitin-Protein Ligases