Influence of preoperative transcatheter arterial chemoembolization on gene expression in the HIF-1α pathway in patients with hepatocellular carcinoma.
OBJECTIVE
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 1α (HIF-1α) could critically affect biology in residual tumors after TACE treatment and subsequent prognosis. However, HIF-1α 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-1α 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-1α and mRNA levels of HIF-1α-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-1α in human specimens treated with TACE. Notably, protein levels of HIF-1α were significantly increased in TACE tissues demonstrated by IHC. Transcriptional targets of HIF-1α showed mRNA expression patterns consistent with activation of HIF-1α in TACE tissues.


CONCLUSIONS
Our findings collectively demonstrate that preoperative TACE confers poor prognosis in HCC patients through activation of HIF-1α.
Department of Surgery, Ajou University School of Medicine, Suwon, 443-721, Korea.
Weiguang
W
Xu
Jung-Hee
JH
Kwon
Young Ho
YH
Moon
Young Bae
YB
Kim
Yun Suk
YS
Yu
Namgyu
N
Lee
Kwan Yong
KY
Choi
Yun Soo
YS
Kim
Yong Keun
YK
Park
Bong Wan
BW
Kim
Hee Jung
HJ
Wang
D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D016461:Chemoembolization, Therapeutic / Q000379:methods; D018572:Disease-Free Survival; D005260:Female; D015870:Gene Expression / Q000235:genetics*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics*; D007150:Immunohistochemistry / Q000379:methods; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D012189:Retrospective Studies
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D012333:RNA, Messenger