Abstract：
Flavonoids exhibit health-promoting benefits against multiple chronic diseases, including cancer. Apigenin (4\',5,7-trihydroxyflavone), one flavonoid present in fruits and vegetables, is potentially applicable to chemoprevention. Despite considerable progress in the therapeutic regimen of liver cancer, its prognosis remains poor. MED28, a Mediator subunit for transcriptional activation, is implicated in the development of several types of malignancy; however, its role in liver cancer is unknown at present. In liver cancer, the AKT/mammalian target of rapamycin (mTOR) is one major pathway involved in the oncogenic process. The aim of this study is to investigate the role of apigenin and MED28 in AKT/mTOR signaling in liver cancer. We first identified a connectivity score of 92.77 between apigenin treatment and MED28 knockdown in several cancer cell lines using CLUE, a cloud-based software platform to assess connectivity among compounds and genetic perturbagens. Higher expression of MED28 predicted a poorer survival prognosis; MED28 expression in liver cancer tissue was significantly higher than that of normal tissue, and it was positively correlated with tumor stage and grade in The Cancer Genome Atlas Liver Cancer (TCGA-LIHC) data set. Knockdown of MED28 induced cell cycle arrest and suppressed the AKT/mTOR signaling in two human liver cancer cell lines, HepG2 and Huh 7, accompanied by less lipid accumulation and lower expression and nuclear localization of sterol regulatory element binding protein 1 (SREBP1). Apigenin inhibited the expression of MED28, and the effect of apigenin mimicked that of the MED28 knockdown. On the other hand, the AKT/mTOR signaling was upregulated when MED28 was overexpressed. These data indicated that MED28 was associated with the survival prognosis and the progression of liver cancer by regulating AKT/mTOR signaling and apigenin appeared to inhibit cell growth through MED28-mediated mTOR signaling, which may be applicable as an adjuvant of chemotherapy or chemoprevention in liver cancer.
摘要：
黄酮类化合物对多种慢性疾病表现出促进健康的益处，包括癌症.芹菜素(4',5,7-三羟基黄酮)，水果和蔬菜中的一种类黄酮，可能适用于化学预防。尽管肝癌的治疗方案取得了相当大的进展，其预后仍然很差。MED28，用于转录激活的介体亚基，与几种恶性肿瘤的发展有关；然而，其在肝癌中的作用目前尚不清楚。在肝癌中，AKT/哺乳动物雷帕霉素靶蛋白(mTOR)是参与致癌过程的一个主要途径。本研究旨在探讨芹菜素和MED28在肝癌AKT/mTOR信号传导中的作用。我们首先使用CLUE在几种癌细胞系中鉴定了芹菜素治疗和MED28敲低之间的连接评分为92.77，一个基于云的软件平台，用于评估化合物和遗传干扰之间的连通性。MED28的高表达预示着预后较差；MED28在肝癌组织中的表达明显高于正常组织，在癌症基因组图谱肝癌（TCGA-LIHC）数据集中，它与肿瘤分期和分级呈正相关。敲低MED28诱导细胞周期停滞和抑制AKT/mTOR信号在两个人肝癌细胞系,HepG2和Huh一7，伴随着较少的脂质积累和较低的固醇调节元件结合蛋白1(SREBP1)的表达和核定位。芹菜素抑制MED28的表达，芹菜素的作用与MED28敲低的作用相似。另一方面,MED28过表达时,AKT/mTOR信号上调.这些数据表明，MED28通过调节AKT/mTOR信号与肝癌的生存预后和进展有关，芹菜素似乎通过MED28介导的mTOR信号抑制细胞生长。可作为肝癌化疗或化学预防的辅助手段。
