Kondo Motoi, Moriishi Kohji, Wada Hiroshi, Noda Takehiro, Marubashi Shigeru, Wakasa Kenichi, Matsuura Yoshiharu, Doki Yuichiro, Mori Masaki, Nagano Hiroaki
Evidence Based Medical Research Center, Osaka;
Exp Ther Med. 2012 Mar;3(3):379-385. doi: 10.3892/etm.2011.415. Epub 2011 Dec 14.
We previously reported that proteasome activator 28γ (PA28γ) is an oncogenic protein in hepatitis C virus (HCV) core protein transgenic mice. The aim of this study was to determine the role of PA28γ expression at the protein level in the development and progression of human hepatocarcinogenesis and hepatocellular carcinoma (HCC). Samples from tissues representing a wide spectrum of liver disease were analyzed, including histologically normal livers (n=5), HCV-related chronic hepatitis (CH) (n=15) and cirrhosis (n=31). The level of nuclear PA28γ increased with the progression of liver disease from CH to cirrhosis. The majority of cirrhotic livers (68%; 21/31) displayed high nuclear PA28γ expression. However, in half of the HCCs (50%; 18/36), little or no nuclear PA28γ expression was observed, while the remaining 50% (18/36) of the cases displayed high levels of nuclear PA28γ expression. A clinicopathological survey demonstrated a significant correlation between nuclear PA28γ expression and capsular invasion in HCC (P=0.026); a striking difference was found between nuclear PA28γ expression in non-tumor tissues and shorter disease-free survival (P<0.01). Moreover, nuclear PA28γ expression in non-tumor tissues correlated with the expression of molecules related to the genesis of hepatic steatosis and HCC, such as sterol regulatory element binding protein-1c mRNA. The findings suggest the involvement of nuclear PA28γ expression in the progression and relapse of HCC, and suggest that nuclear PA28γ is a potentially suitable target for the prevention and/or treatment of HCC.
我们之前报道过，蛋白酶体激活因子28γ（PA28γ）在丙型肝炎病毒（HCV）核心蛋白转基因小鼠中是一种致癌蛋白。本研究的目的是确定PA28γ蛋白表达在人类肝癌发生和肝细胞癌（HCC）发展及进展中的作用。分析了代表广泛肝脏疾病的组织样本，包括组织学正常的肝脏（n = 5）、HCV相关慢性肝炎（CH）（n = 15）和肝硬化（n = 31）。核PA28γ水平随着肝脏疾病从CH进展到肝硬化而升高。大多数肝硬化肝脏（68%；21/31）显示出高核PA28γ表达。然而，在一半的HCC中（50%；18/36），观察到很少或没有核PA28γ表达，而其余50%（18/36）的病例显示出高水平的核PA28γ表达。一项临床病理调查显示，HCC中核PA28γ表达与包膜侵犯之间存在显著相关性（P = 0.026）；在非肿瘤组织中核PA28γ表达与较短的无病生存期之间发现了显著差异（P < 0.01）。此外，非肿瘤组织中的核PA28γ表达与肝脂肪变性和HCC发生相关分子的表达相关，如固醇调节元件结合蛋白-1c mRNA。这些发现提示核PA28γ表达参与了HCC的进展和复发，并表明核PA28γ是HCC预防和/或治疗的潜在合适靶点。
