Deregulation of HIF1-alpha and hypoxia-regulated pathways in hepatocellular carcinoma and corresponding non-malignant liver tissue—influence of a modulated host stroma on the prognosis of HCC

Abstract

The aim of this study was to elucidate the role of HIF1A expression in hepatocellular carcinoma (HCC) and the corresponding non-malignant liver tissue and to correlate it with the clinical outcome of HCC patients after curative liver resection. HIF1A expression was determined by quantitative RT-PCR in HCC and corresponding non-malignant liver tissue of 53 patients surgically treated for HCC. High-density gene expression analysis and pathway analysis was performed on a selected subset of patients with high and low HIF1A expression in the non-malignant liver tissue. HIF1A over-expression in the apparently non-malignant liver tissue was a predictor of tumor recurrence and survival. The estimated 1-year and 5-year disease-free survival was significantly better in patients with low HIF1A expression in the non-malignant liver tissue when compared to those patients with high HIF1 expression (88.9% vs. 67.9% and 61.0% vs. 22.6%, respectively, p = 0.008). Based on molecular pathway analysis utilizing high-density gene-expression profiling, HIF1A related molecular networks were identified that contained genes involved in cell migration, cell homing, and cell-cell interaction. Our study identified a potential novel mechanism contributing to prognosis of HCC. The deregulation of HIF1A and its related pathways in the apparently non-malignant liver tissue provides for a modulated environment that potentially enhances or allows for HCC recurrence after curative resection.