LRH-1 drives hepatocellular carcinoma partially through induction of c-myc and cyclin E1, and suppression of p21.
LRH-1 drives hepatocellular carcinoma partially through induction of c-myc and cyclin E1, and suppression of p21.
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LRH-1 部分通过诱导 c-myc 和细胞周期蛋白 E1 以及抑制 p21 驱动肝细胞癌
DOI：
10.2147/cmar.s162887
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发表时间：
2018
影响因子：
3.3
通讯作者：
Zhou Y
中科院分区：
文献类型：
--
作者：
Xiao L;Wang Y;Liang W;Liu L;Pan N;Deng H;Li L;Zou C;Chan FL;Zhou Y
背景探索潜在的治疗靶点是临床和基础肝细胞癌研究的热点之一。近年来，核受体肝受体同源物-1 （LRH-1, NR5A2）被证实在乳腺癌、胰腺癌、肠癌等多种癌症中发挥积极作用。然而，LRH-1在HCC发生发展中的确切作用尚未完全阐明。方法采用免疫组化（IHC）法检测肝细胞癌临床标本中LRH-1的表达水平。利用转录激活因子样效应核酸酶（TALENs）生成了稳定的lrh -1抑制HepG2克隆（HepG2LRH-1/-），并进行了体外和体内实验。结果我们证实LRH-1在HCC临床样本中表现出增高的表达模式。体外和体内实验结果表明，抑制LRH-1可显著降低HepG2的增殖速率和致瘤能力。基因表达芯片分析表明，lrh -1主要调控与细胞周期相关的基因表达。此外，我们的功能获得实验表明，LRH-1的异位表达显著诱导了c-myc和cyclin E1的mRNA和蛋白水平，同时减弱了p21的表达。结论LRH-1可能是HCC临床治疗的潜在靶点。
Background To explore potential therapeutic target is one of the areas of great interest in both clinical and basic hepatocellular carcinoma (HCC) studies. Nuclear receptor liver receptor homolog-1 (LRH-1, NR5A2) is proved to play a positive role in several cancers including breast cancer, pancreatic cancer and intestinal cancer in recent years. However, the exact role of LRH-1 in the development and progression of HCC is not fully elucidated. Methods The LRH-1 expression level in HCC clinical samples was examined by immunohis-tochemistry (IHC). Stable LRH-1-suppressed HepG2 clones (HepG2LRH-1/-) were generated by transcription activator-like effector nucleases (TALENs) and both in vitro and in vivo experiments were conducted. Results We confirmed that LRH-1 showed an increased expression pattern in HCC clinical samples. Our in vitro and in vivo results indicated that suppression of LRH-1 in HepG2 significantly attenuated its proliferation rate and tumorigenic capacity. Gene expression microarray analysis indicated that LRH-1mostly regulated gene expression involved in cell cycle. In addition, our gain-of-function experiments indicated that ectopic expression of LRH-1 dramatically induced the mRNA and protein levels of c-myc and cyclin E1, while attenuating the expression of p21. Conclusion Our results suggest that LRH-1 might be a potential therapeutic target for clinical HCC treatment.