title: Tg737 signaling is required for hypoxia-enhanced invasion and migration of hepatoma cells.
abstract: BACKGROUND
  Although hypoxia is known to promote hepatoma cell invasion and migration, little is known regarding the molecular mechanisms of this process. Our previous research showed that loss of Tg737 is associated with hepatoma cell invasion and migration; therefore, we hypothesized that the Tg737 signal might be required for hypoxia-enhanced invasion and migration.
  
  
  METHODS
  We established in vitro normoxic or hypoxic models to investigate the role of Tg737 in the hypoxia-enhanced invasion and migration of hepatoma cells. The hepatoma cell lines HepG2 and MHCC97-H were subjected to normoxic or hypoxic conditions, and the cell adhesion, invasion, and migration capabilities were tested. The expression of Tg737 under normoxia or hypoxia was detected using western blot assays; cell viability was determined using flow cytometry. Furthermore, we created HepG2 and MHCC97-H cells that over expressed Tg737 prior to incubation under hypoxia and investigated their metastatic characteristics. Finally, we analyzed the involvement of critical molecular events known to regulate invasion and migration.
  
  
  RESULTS
  In this study, Tg737 expression was significantly inhibited in HepG2 and MHCC97-H cells following exposure to hypoxia. The down regulation of Tg737 expression corresponded to significantly decreased adhesion and increased invasion and migration. Hypoxia also decreased the expression/secretion of polycystin-1, increased the secretion of interleukin-8 (IL-8), and increased the levels of active and total transforming growth factor β 1 (TGF-β1), critical regulators of cell invasion and migration. Moreover, the decrease in adhesiveness and the increase in the invasive and migratory capacities of hypoxia-treated hepatoma cells were attenuated by pcDNA3.1-Tg737 transfection prior to hypoxia. Finally, following the up regulation of Tg737, the expression/secretion of polycystin-1 increased, and the secretion of IL-8 and the levels of active and total TGF-β1 decreased correspondingly.
  
  
  CONCLUSIONS
  These data provide evidence that Tg737 contributes to hypoxia-induced invasion and migration, partially through the polycystin-1, IL-8, and TGF-β1 pathway. Taken together, this work suggests that Tg737 is involved in the invasion and migration of hepatoma cells under hypoxia, with the involvement of the polycystin-1, IL-8, and TGF-β1 signaling pathway. Tg737 is a potential therapeutic target for inhibiting the high invasion and migration potential of hepatoma cells in hypoxic regions.
authors.affiliation: Department of Hepatobiliary Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an 710032, China.
authors.forename: Nan
authors.initials: N
authors.lastname: You
authors.forename: Weihui
authors.initials: W
authors.lastname: Liu
authors.forename: Lijun
authors.initials: L
authors.lastname: Tang
authors.forename: Xiao
authors.initials: X
authors.lastname: Zhong
authors.forename: Ru
authors.initials: R
authors.lastname: Ji
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Desheng
authors.initials: D
authors.lastname: Wang
authors.forename: Yong
authors.initials: Y
authors.lastname: He
authors.forename: Kefeng
authors.initials: K
authors.lastname: Dou
authors.forename: Kaishan
authors.initials: K
authors.lastname: Tao
mesh_terms: D006528:Carcinoma, Hepatocellular / Q000378:metabolism; D015687:Cell Hypoxia; D002465:Cell Movement / Q000235:genetics*; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D056945:Hep G2 Cells; D006801:Humans; D016209:Interleukin-8 / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000235:genetics*; D015398:Signal Transduction; D050396:TRPP Cation Channels / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016209:Interleukin-8; D050396:TRPP Cation Channels; D053773:Transforming Growth Factor beta1; D025521:Tumor Suppressor Proteins; C098623:IFT88 protein, human