Obulhasim Gulanbar, Yasen Mahmut, Kajino Kazunori, Mogushi Kaoru, Tanaka Shinji, Mizushima Hiroshi, Tanaka Hiroshi, Arii Shigeki, Hino Okio
Department of Pathology and Oncology, Juntendo University School of Medicine, 2-1-1, Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Department of Surgery, Xinjiang Uyghur Tumor Hospital of Xinjiang Medical University, 30 Beijing Rood, Urumqi, 830011, Xinjiang, China.
Hepatol Int. 2013 Mar;7(1):215-25. doi: 10.1007/s12072-012-9357-4. Epub 2012 Mar 13.
Metabolic syndrome (MS) is a group of recognized risk factors for the development of hepatocellular carcinoma (HCC) in patients with chronic liver disease. The aim of this study was to analyze the clinicopathological characteristics of HCC patients with MS and the risk factors for recurrence. Also, the aim was to investigate the cold shock protein: DNA-binding protein A (dbpA) expression in HCC patients with MS.
A total of 243 patients who underwent curative resections for HCC were classified into two groups. dbpA expression was investigated in 66 HCC patients with MS and in 30 patients without MS by using real-time RT-PCR. Promoter methylation status was examined by using MS-PCR.
The incidence of metabolic factors affect the HCC significantly higher in non-B non-C patients than in hepatitis B virus (HBV) or hepatitis C virus (HCV) patients (P < 0.001). Univariate analysis of HCC patients with MS recurrence revealed aspartate amino transferase (AST), multiple tumors, liver damage, hepatic vein invasion, advanced cancer stages (P < 0.01), alpha-fetoprotein (AFP) and diabetes mellitus type II (P < 0.05) as risk factors. Multivariate analysis, AST, multiple tumors, and hepatic vein invasion (P < 0.01) were identified as independent factors for the recurrence. dbpA mRNA was higher in patients with MS than in those without MS (P = 0.016), and it was mostly upregulated in non-B non-C HCC patients with MS than in non-B non-C HCC patients without HBV or HCV. Especially, in HCC patients with diabetes mellitus type II, the mRNA and protein levels were highly upregulated. The dbpA expression was regulated by promoter methylation status (P < 0.05).
This study identifies that dbpA may accelerate the hepatocarcinogenesis in HCC patients with MS via inflammation-induced and oxidative stress pathways. The demethylation-related epigenetic activation may be one of the regulating factors for HCC patients with MS.
代谢综合征（MS）是慢性肝病患者发生肝细胞癌（HCC）的一组公认危险因素。本研究旨在分析MS合并HCC患者的临床病理特征及复发危险因素。此外，旨在研究MS合并HCC患者中冷休克蛋白：DNA结合蛋白A（dbpA）的表达情况。
将243例行HCC根治性切除术的患者分为两组。采用实时逆转录聚合酶链反应（RT-PCR）检测66例MS合并HCC患者和30例无MS患者的dbpA表达。采用甲基化特异性聚合酶链反应（MS-PCR）检测启动子甲基化状态。
非B非C型患者中影响HCC的代谢因素发生率显著高于乙型肝炎病毒（HBV）或丙型肝炎病毒（HCV）患者（P<0.001）。对MS合并HCC复发患者的单因素分析显示，天冬氨酸氨基转移酶（AST）、多发肿瘤、肝损伤、肝静脉侵犯、癌症晚期（P<0.01）、甲胎蛋白（AFP）和II型糖尿病（P<0.05）为危险因素。多因素分析显示，AST、多发肿瘤和肝静脉侵犯（P<0.01）是复发的独立因素。MS患者的dbpA信使核糖核酸（mRNA）高于无MS患者（P=0.016），且在非B非C型MS合并HCC患者中比非B非C型无HBV或HCV的HCC患者中上调更为明显。特别是，在II型糖尿病合并HCC患者中，mRNA和蛋白水平上调程度更高。dbpA表达受启动子甲基化状态调控（P<0.05）。
本研究表明，dbpA可能通过炎症诱导和氧化应激途径加速MS合并HCC患者的肝癌发生。去甲基化相关的表观遗传激活可能是MS合并HCC患者的调控因素之一。
