Abstract
BackgroundAlthough 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.MethodsWe 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.ResultsIn 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.ConclusionsThese 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.
Highlights
Hypoxia is known to promote hepatoma cell invasion and migration, little is known regarding the molecular mechanisms of this process
We showed that loss of heterozygosity (LOH) of the Tg737 gene at markers SHGC-57879 and G64212 closely correlates with tumor node metastasis (TNM) stage and with Hepatocellular carcinoma (HCC) metastasis, indicating that these two markers can be detected independently and used to predict tumor stage and metastasis in HCC patients [7]
Polycystin-1, IL-8, and transforming growth factor β 1 (TGF-β1) were associated with the contribution of Tg737 to hypoxia-induced adhesion, migration, and invasion To further explore the mechanism of action of Tg737 in hypoxia-induced adhesion, migration, and invasion in HCC cells, we examined the effects of Tg737 on the expression/secretion of polycystin-1 and the secretion of IL-8 and TGF-β1, critical regulators of cell invasion and migration
Summary
Hypoxia is known to promote hepatoma cell invasion and migration, little is known regarding the molecular mechanisms of this process. Invasion and metastasis have become major challenges that must be overcome for the effective treatment of HCC. Advances in treatments for this disease are likely to develop from a better understanding of the mechanisms of invasion and metastasis. In HCC, tissue oxygenation measurements have revealed large areas of hypoxic tissue, and the expression of hypoxic markers has been correlated with rapid invasion and metastasis, short overall survival, and short time to recurrence. Cells invasion and metastasis involve several sequential steps and a large number of altered molecules (such as cytokines, chemokines and their receptors, and growth factors) [4,5]. The precise and key molecular events that initiate this crucial turning point remain unknown, and this knowledge gap can lead to delays in diagnosis and poor treatment
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