Hypoxia-inducible factor-1 alpha, in association with inflammation, angiogenesis and MYC, is a critical prognostic factor in patients with HCC after surgery

Chen-Xin Dai,Ming-Yan Cai,Min-Jie Ju,Jian Zhou,Bo-Heng Zhang,Yong-Feng Xu,Jia Fan,Qiang Gao,Shuang-Jian Qiu

doi:10.1186/1471-2407-9-418

Abstract

BackgroundDespite well-studied tumor hypoxia in laboratory, little is known about the association with other pathophysiological events in the clinical view. We investigated the prognostic value of hypoxia-inducible factor-1 alpha (HIF-1alpha) in hepatocellular carcinoma (HCC), and its correlations with inflammation, angiogenesis and MYC oncogene.MethodsIn a random series of 110 HCC patients, the mRNA of HIF-1alpha, inflammation related factors (COX-2, MMP7 and MMP9), angiogenesis related factors (VEGF and PDGFRA) and MYC in tumor tissue were detected by real-time RT-PCR and HIF-1alpha protein was assessed by immunohistochemistry. The correlations between HIF-1alpha mRNA and the factors mentioned previously, the relationship between HIF-1alpha and clinicopathologic features, and the prognostic value were analyzed.ResultsThe expression of both HIF-1alpha mRNA and protein in HCC were independent prognostic factors for overall survival (OS) (P = 0.012 and P = 0.021, respectively) and disease-free survival (DFS) (P = 0.004 and P = 0.007, respectively) as well. Besides, the high expression of HIF-1alpha mRNA and protein proposed an advanced BCLC stage and more incidence of vascular invasion. The mRNA of HIF-1alpha had significantly positive correlations to that of COX-2, PDGFRA, MMP7, MMP9, MYC, except VEGF. In addition to HIF-1alpha, COX-2 and PDGFRA were also independent prognosticators for OS (P = 0.004 and P = 0.010, respectively) and DFS (P = 0.010 and P = 0.038, respectively).ConclusionHIF-1alpha in HCC plays an important role in predicting patient outcome. It may influence HCC biological behaviors and affect the tumor inflammation, angiogenesis and act in concert with the oncogene MYC. Attaching importance to HIF-1alpha in HCC may improve the prognostic and therapeutic technique.

Highlights

Despite well-studied tumor hypoxia in laboratory, little is known about the association with other pathophysiological events in the clinical view
We presented the real-time reverse-transcriptase polymerise-chain-reaction (RT-PCR) study in the same cohort of patients on a battery of core genes which play important roles in inflammation (COX2, MMP7, MMP9) [14,15,16] and angiogenesis (VEGF, platelet-derived growth factor receptor (PDGFRA)) [17,18], as well as MYC which was confirmed as a key hypoxia regulator [19], to find the correlation of HIF1α with these factors that can affect and reflect tumor behaviors
Correlation of HIF-1 mRNA to clinicopathologic features According to the optimal cut-point value of hypoxiainducible factor-1α (HIF-1α) determined by the X-tile software, the expression of HIF-1α mRNA was defined as high expression in 42 specimens (38.2%) and low expression in 68 specimens (61.8%)

Summary

Introduction

Despite well-studied tumor hypoxia in laboratory, little is known about the association with other pathophysiological events in the clinical view. We investigated the prognostic value of hypoxia-inducible factor-1 alpha (HIF-1alpha) in hepatocellular carcinoma (HCC), and its correlations with inflammation, angiogenesis and MYC oncogene. As is well-recognized, hypoxia is a common mechanism in HCC as the solid tumor owing to aberrant visualization [2]. Accumulating data have shown that hypoxia can stimulate proliferation[3], induce angiogenesis [4], accelerate invasion [5] and is responsible for treatment resistance in HCC [6]. The adaptation of HCC cells to tissue hypoxia is of central importance for tumor progression, where inducing the ubiquitous transcription factor of hypoxiainducible factor-1α (HIF-1α) expression appears to be a critical step [7]

Methods

Results

Discussion

Conclusion