Department of Surgery, Institute of Health Biosciences, The University of Tokushima Graduate School, Tokushima, Japan.
Surgery. 2012 Mar;151(3):412-9. doi: 10.1016/j.surg.2011.07.038. Epub 2011 Oct 8.
Histone deacetylase (HDAC) plays an important role in chromatin remodeling and gene expression, and in regulating cell cycle progression and differentiation. Furthermore, hypoxic conditions in the malignant tumor enhance HDAC function and increased HDAC activity is closely involved in worse malignant behavior through hypoxia inducible factor (HIF) activation. The aim of this study was to elucidate the correlation between HDAC expression and tumor malignant behavior including HIF-1α expression in intrahepatic cholangiocarcinoma (IHCC).
Thirty-five patients with IHCC who underwent hepatic resection were evaluated. HDAC1 and HIF-1α expressions were determined immunohistochemically, and the patients were divided into 2 groups: the HDAC1 positive group (n = 21) and the HDAC1 negative group (n = 14). Clinicopathologic variables including HIF-1α expression were compared between the 2 groups.
HDAC1 expression correlated significantly with higher stage carcinoma, lymph node metastasis, and vascular invasion. The prognosis in the HDAC1 positive group was poorer than in the HDAC1 negative group (5-year survival: 78% vs 8%, P = .001). Furthermore, disease free survival rate in the HDAC1 positive group had significantly worse than that in the HDAC1 negative group (P = .0003). In the multivariate analysis, HDAC1 positive expression was identified as the only independent prognostic factor for disease free survival (Hazard Ratio: 7.194, P = .0018). Furthermore, there was a significant correlation between HDAC1 expression and HIF-1α expression (P = .007).
These findings suggested that HDAC1 positive expression was a potential new prognostic indicator of IHCC, and a possible promising molecular target through the regulation of HIF-1α.
组蛋白去乙酰化酶（HDAC）在染色质重塑和基因表达、细胞周期进程和分化的调控中起着重要作用。此外，恶性肿瘤中的缺氧条件增强了 HDAC 的功能，并且通过缺氧诱导因子（HIF）的激活，增加的 HDAC 活性与更差的恶性行为密切相关。本研究旨在阐明 HDAC 表达与包括肝内胆管癌（IHCC）中 HIF-1α表达在内的肿瘤恶性行为之间的相关性。
评估了 35 例接受肝切除术的 IHCC 患者。通过免疫组织化学法测定 HDAC1 和 HIF-1α的表达，并将患者分为 HDAC1 阳性组（n = 21）和 HDAC1 阴性组（n = 14）。比较两组之间的临床病理变量，包括 HIF-1α的表达。
HDAC1 表达与较高分期的癌、淋巴结转移和血管侵犯显著相关。HDAC1 阳性组的预后比 HDAC1 阴性组差（5 年生存率：78%比 8%，P =.001）。此外，HDAC1 阳性组的无病生存率明显低于 HDAC1 阴性组（P =.0003）。在多变量分析中，HDAC1 阳性表达被确定为无病生存的唯一独立预后因素（危险比：7.194，P =.0018）。此外，HDAC1 表达与 HIF-1α表达之间存在显著相关性（P =.007）。
这些发现表明，HDAC1 阳性表达是 IHCC 的一个潜在新的预后指标，通过调节 HIF-1α，可能成为一个有前途的分子靶点。
