Abstract
BackgroundHepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. The 5-year survival rate remains low despite considerable research into treatments of HCC, including surgery, radiotherapy and chemotherapy. Many mechanisms within HCC still require investigation, including the influence of hypoxia, which has a crucial role in many cancers and is associated with metastasis. Hypoxia inducible factor-1α (HIF-1α) is known to regulate the expression of many chemokines, including interleukin-8 (IL-8), which is associated with tumor metastasis. Although many studies have reported that HIF-1α is associated with HCC migration and invasion, the underlying mechanisms remain unknown.MethodsThe expression level of HIF-1α was determined in HCC cells. The correlation of IL-8 and HIF-1α expressions was assessed via knockdown of HIF-1α. HCC cells were also used to assess the influence of HIF-1α on HCC cell migration and invasion. LY294002, an inhibitor of the Akt pathway, was used to confirm the associated signaling pathways.ResultsWe observed a significant attenuation of cell migration and invasion after silencing of HIF-1α. Exogenously expressing IL-8 restored migration and invasion. Akt was found to be involved in this process.ConclusionHypoxia promotes HCC cell migration and invasion through the HIF-1α–IL-8–Akt axis.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide
We found that IL-8 is regulated by hypoxia induced-Hypoxia inducible factor-1α (HIF-1α) and that it can restore HCC cell migration and invasion attenuated by knockdown of HIF-1α
The mRNA level of HIF-1α was significantly higher in both HCC cell lines than in WRL68 under hypoxia, while there were no statistical differences between the HIF-1α expression levels for the three cell lines under normoxia (Fig. 1a)
Summary
Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third most common cause of cancer-related death worldwide. The 5-year survival rate remains low despite considerable research into treatments of HCC, including surgery, radiotherapy and chemotherapy. Many mechanisms within HCC still require investigation, including the influence of hypoxia, which has a crucial role in many cancers and is associated with metastasis. Hypoxia inducible factor-1α (HIF-1α) is known to regulate the expression of many chemokines, including interleukin-8 (IL-8), which is associated with tumor metastasis. Many studies have reported that HIF-1α is associated with HCC migration and invasion, the underlying mechanisms remain unknown. Advances have been made in diagnostic and treatment strategies, the 5-year survival rate remains low because of the high rates of metastasis [2, 3]. Several pathogenic mechanisms and factors associated with HCC have been documented, but the molecular mechanisms of HCC migration and invasion still need investigation [4]. Recent studies showed that HIF-1α has a role in HCC cell
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