Ni Lulu, Sun Ping, Fan Xiaochun, Li Zhongjie, Ren Hongli, Li Jiangan
Department of Basic Medicine, Jiangnan University, Wuxi, China.
Department of Pathology, The Affiliated Wuxi NO. 2 People's Hospital of Nanjing Medical University, Wuxi, China.
Front Pharmacol. 2022 Jan 31;12:775514. doi: 10.3389/fphar.2021.775514. eCollection 2021.
Berberine is one of the most interesting and promising natural anticancer drugs. POLE2 is involved in many cellular functions such as DNA replication and is highly expressed in a variety of cancers. However, the specific molecular mechanism of berberine interfering with POLE2 expression in lung adenocarcinoma (LUAD) is still unknown to a great extent. The KEGG database (Release 91.0) and Gene Ontology (GO) category database were used for functional annotation of differentially expressed genes after berberine treatment. Reproducibility assessment using TCGA dataset. The biological functions of berberine in LUAD were investigated by a series of and experiments: MTT, colony formation, mouse xenograft and plasmid transfection. The molecular mechanisms of berberine were demonstrated by plasmid transfection, quantitative RT-PCR and Western blotting. The elevated expression of FOXM1 and the high enrichment of DNA replication pathway were confirmed in LUAD by microarray and TCGA analysis, and were positively correlated with poor prognosis. Functionally, berberine inhibited the proliferation and survival of LUAD cell lines and . Mechanistically, berberine treatment down regulated the expression of FOXM1which closely related to survival, survival related genes in Cell cycle and DNA replication pathway, and significantly down regulated the expression of survival related POLE2. Interestingly, we found that the transcription factor FOXM1 could act as a bridge between berberine and POLE2. Berberine significantly inhibited LUAD progression via the FOXM1/POLE2, and FOXM1/POLE2 may act as a clinical prognostic factor and a therapeutic target for LUAD. Berberine may be used as a promising therapeutic candidate for LUAD patients.
小檗碱是最具吸引力和前景的天然抗癌药物之一。POLE2参与DNA复制等多种细胞功能，在多种癌症中高表达。然而，小檗碱干扰肺腺癌（LUAD）中POLE2表达的具体分子机制在很大程度上仍不清楚。使用KEGG数据库（版本91.0）和基因本体（GO）类别数据库对小檗碱处理后差异表达基因进行功能注释。利用TCGA数据集进行可重复性评估。通过一系列实验（MTT、集落形成、小鼠异种移植和质粒转染）研究小檗碱在LUAD中的生物学功能。通过质粒转染、定量RT-PCR和蛋白质印迹法证明小檗碱的分子机制。通过微阵列和TCGA分析证实LUAD中FOXM1表达升高和DNA复制途径高度富集，且与不良预后呈正相关。功能上，小檗碱抑制LUAD细胞系的增殖和存活。机制上，小檗碱处理下调与存活密切相关的FOXM1、细胞周期和DNA复制途径中与存活相关的基因的表达，并显著下调与存活相关的POLE2的表达。有趣的是，我们发现转录因子FOXM1可作为小檗碱和POLE2之间的桥梁。小檗碱通过FOXM1/POLE2显著抑制LUAD进展，且FOXM1/POLE2可能作为LUAD的临床预后因素和治疗靶点。小檗碱可能成为LUAD患者有前景的治疗候选药物。
