肝积方下调ARPP-19表达抑制肝细胞性肝癌肿瘤生长(英文)

Ganji Formula inhibits tumor growth of hepatocellular carcinoma through down-regulating ARPP-19 expression

肝细胞性肝癌(HCC)是最常见的恶性肿瘤之一,迄今仍缺乏有效的治疗方法。临床观察显示,中药复方肝积方对肝癌有治疗作用。本研究旨在评价肝积方对HCC的作用和安全性,并初步探讨其潜在的分子机制。选用BALB/c裸鼠建立皮下肝癌异种移植模型,灌胃给予肝积方干预后,观察肿瘤生长和肝、肾组织形态学变化,检测cAMP调节的磷酸化蛋白19(ARPP-19)及细胞分裂调控相关分子的表达,并动态观察荷瘤小鼠存活情况。结果显示,肝积方干预后,荷瘤小鼠体质量和活动能力均有明显改善,存活时间有延长趋势,肝、肾组织未见明显损伤,肿瘤体积和质量呈剂量依赖性降低,肿瘤增殖指数及癌组织增殖细胞核抗原(PCNA)表达均低于对照组。此外,肝积方可下调ARPP-19以及周期素依赖性激酶(Cdks)底物磷酸化水平,上调失活的细胞分裂周期蛋白2(Cdc2)表达水平。这些结果表明,肝积方可有效抑制HCC小鼠肿瘤生长,改善荷瘤裸鼠生存状态,其作用机制可能与下调ARPP-19表达、抑制HCC细胞有丝分裂和细胞增殖有关。研究结果将为该复方的临床应用提供实验依据。

Hepatocellular carcinoma(HCC) is one of the most common malignant tumors. Rare effective treatment is available for HCC patients at present. Ganji Formula, one formula of traditional Chinese medicine(TCM), has shown therapeutic effect on HCC in clinical observation. This study aims to evaluate the effect and safety of Ganji Formula on HCC, and explore the potential molecular mechanism. HCC subcutaneous xenograft model was established in BALB/c nude mice, which treated with Ganji Formula by intragastric administration. The tumor growth and the histopathology of liver and kidney were observed. The expressions of cAMP-regulated phosphoprotein 19(ARPP-19) and the related cell mitosis regulatory molecules were measured. The survival of tumor bearing mice with or without Ganji Formula treatment was recorded dynamically. The results showed that, the body weight and activity of Ganji Formula-treated mice were improved obviously,with the tendency of prolonging survival time. No obvious injury was observed in tissues of liver and kidney. The tumor volume and mass was significantly down-regulated in a dose-dependent manner. The tumor proliferation index and the expression of proliferating cell nuclear antigen( PCNA) in tumor tissue were lower than those in the control group. Furthermore,Ganji Formula down-regulated the levels of ARPP-19 and phosphorylated cyclin dependent kinases( Cdks) substrates,up-regulated the level of inactivated cyclin division cycle 2( Cdc2). These results indicate that Ganji Formula can effectively inhibit tumor growth of HCC and improve the survival status of tumor bearing nude mice. The mechanism is partially related to down-regulating ARPP-19 expression to inhibit mitosis and cell proliferation of HCC. It will provide experimental basis for the clinical application of Ganji Formula.