Influence of preoperative transcatheter arterial chemoembolization on gene expression in the HIF-1α pathway in patients with hepatocellular carcinoma.

Abstract

PURPOSE: Although transcatheter arterial chemoembolization (TACE) is the most

common treatment option in patients with hepatocellular carcinoma (HCC), its

clinical benefits remain still controversial. Since TACE induces hypoxic necrosis

in tumors, hypoxia-inducible factor 1alpha (HIF-1alpha) could critically affect

biology in residual tumors after TACE treatment and subsequent prognosis.

However, HIF-1alpha and its prognostic relevance in TACE have rarely been

examined in human specimens. In the current study, we investigated the prognosis

and expression of genes regulated by HIF-1alpha in HCC patients receiving

preoperative TACE for the first time. METHODS: In total, 35 patients with HCC (10

patients undergoing preoperative TACE) were retrospectively studied. The

prognostic significance of TACE was analyzed using Kaplan-Meier and Cox

regression models. Protein levels of HIF-1alpha and mRNA levels of

HIF-1alpha-associated genes were examined using immunohistochemistry (IHC) and

real-time RT-PCR, respectively. RESULTS: Preoperative TACE was significantly

associated with increased 2-year recurrence rate (80 vs. 36 %, P = 0.00402) and

shorter disease-free survival (DFS) time (11.9 vs. 35.7 months, P = 0.0182). TACE

was an independent prognostic factor for recurrence (P = 0.007) and poor DFS (P =

0.010) in a multivariate analysis. Immunohistochemical staining revealed in vivo

activation of HIF-1alpha in human specimens treated with TACE. Notably, protein

levels of HIF-1alpha were significantly increased in TACE tissues demonstrated by

IHC. Transcriptional targets of HIF-1alpha showed mRNA expression patterns

consistent with activation of HIF-1alpha in TACE tissues. CONCLUSIONS: Our

findings collectively demonstrate that preoperative TACE confers poor prognosis

in HCC patients through activation of HIF-1alpha.