Liver-enriched activator protein 1 as an isoform of CCAAT/enhancer-binding protein beta suppresses stem cell features of hepatocellular carcinoma.
Liver-enriched activator protein 1 as an isoform of CCAAT/enhancer-binding protein beta suppresses stem cell features of hepatocellular carcinoma.
复制标题
富含肝脏的激活蛋白 1 作为 CCAAT/增强子结合蛋白 β 的亚型抑制肝细胞癌的干细胞特征
DOI：
10.2147/cmar.s160172
复制
发表时间：
2018
影响因子：
3.3
通讯作者：
Hu YP
中科院分区：
文献类型：
--
作者：
Yang LH;Wang Y;Qiao S;Wang MJ;Chen F;Zi XY;Li JX;Zhang HB;Yu B;Hu YP
目的肝癌干细胞（CSCs）与肝癌的发生、生存、增殖、转移和复发密切相关。本研究旨在探讨肝脏富集激活蛋白1（liver-enriched activator protein 1，LAP 1）与肝细胞癌（hepatocellular carcinoma，HCC）和肝干细胞（liver CSCs，LCSCs）的关系，并探讨LAP 1对LCSCs的影响。材料与方法采用免疫印迹、实时荧光定量PCR、免疫组化和流式细胞术分析肝癌组织与癌旁肝组织、LCSC与非CSC中LAP 1表达的差异。通过体外CSC标志物表达、六钩蚴形成、增殖、迁移和侵袭来评价LAP 1对肝癌细胞的作用。分析细胞周期分布和凋亡细胞的数量，以评估细胞周期和细胞凋亡。此外，建立了小鼠皮下移植瘤模型，以探讨LAP 1在体内肝癌发生发展中的作用。最后，通过免疫荧光法评估石蜡包埋切片中CSC标志物的表达。结果LAP 1在肝癌组织和肝癌细胞系中表达较弱，在肝细胞癌干细胞中表达更弱。LAP 1抑制干细胞相关基因的表达，降低六钩蚴的形成、增殖、迁移和侵袭能力。细胞周期分析显示，LAP 1可诱导G1/G 0期阻滞。此外，LAP 1降低皮下肿瘤形成能力和CSC标志物和Ki 67的表达。结论LAP 1抑制肝癌干细胞特性，提示其在体内外均具有抗肝癌作用，可能成为肝癌靶向治疗的潜在靶点。
Purpose Liver cancer stem cells (CSCs) are known to be associated with the development, survival, proliferation, metastasis, and recurrence of liver tumors. The aim of this study was to investigate the association of liver-enriched activator protein 1 (LAP1) with hepatocellular carcinoma (HCC) and liver CSCs (LCSCs) and explore the impact of LAP1 on LCSCs. Materials and methods Differences in LAP1 expression in liver cancer tissues versus matched para-tumoral liver tissues and LCSCs versus non-CSCs were analyzed by Western blotting, real-time polymerase chain reaction, immunohistochemistry, and flow cytometry. The effect of LAP1 on liver cancer cells was evaluated by the expression of CSC markers, oncosphere formation, proliferation, migration, and invasion in vitro. Cell cycle distribution and the number of apoptotic cells were analyzed to assess cell cycle and cell apoptosis. Furthermore, a mouse subcutaneous tumor implant model was established to explore the role of LAP1 in the development of HCC in vivo. Finally, the expression of CSC markers in paraffin-embedded sections was evaluated by immunofluorescence. Results LAP1 was weakly expressed in HCC tumors and cell lines and even weaker in LCSCs. LAP1 inhibited the expression of stem cell–associated genes and reduced the abilities of oncosphere formation, proliferation, migration, and invasion in vitro. Cell cycle assay revealed that LAP1 induced G1/G0 arrest. Furthermore, LAP1 decreased subcutaneous tumor-formation ability and the expression of CSC markers and Ki67 in vivo. Conclusion LAP1 suppressed the stem cell features of HCC, indicating that it possessed an antitumor effect in liver cancer, both in vitro and in vivo; therefore, LAP1 may prove to be a potential target in liver CSC-targeted therapy.