The Core-Targeted RRM2 Gene of Berberine Hydrochloride Promotes Breast Cancer Cell Migration and Invasion via the Epithelial-Mesenchymal Transition

作者全名："He, Jiaming; Wei, Qiang; Jiang, Rong; Luan, Tiankuo; He, Shuang; Lu, Ruijin; Xu, Hang; Ran, Jianhua; Li, Jing; Chen, Dilong"

作者地址："[He, Jiaming; Jiang, Rong; He, Shuang; Lu, Ruijin; Li, Jing; Chen, Dilong] Chongqing Med Univ, Coll Basic Med, Dept Histol & Embryol, Lab Stem Cells & Tissue Engn, Chongqing 400016, Peoples R China; [Wei, Qiang] Chongqing Med Univ, Affiliated Hosp 1, Dept Lab Med, Chongqing 400016, Peoples R China; [Luan, Tiankuo; Xu, Hang; Ran, Jianhua] Chongqing Med Univ, Coll Basic Med, Neurosci Res Ctr, Chongqing 400016, Peoples R China; [Chen, Dilong] Chongqing Three Gorges Med Coll, Chongqing Key Lab Dev & Utilizat Genuine Med Mat T, Chongqing 404120, Peoples R China"

通信作者："Li, J; Chen, DL (通讯作者)，Chongqing Med Univ, Coll Basic Med, Dept Histol & Embryol, Lab Stem Cells & Tissue Engn, Chongqing 400016, Peoples R China.; Chen, DL (通讯作者)，Chongqing Three Gorges Med Coll, Chongqing Key Lab Dev & Utilizat Genuine Med Mat T, Chongqing 404120, Peoples R China."

来源：PHARMACEUTICALS

ESI学科分类：　

WOS号：WOS:000916394000001

JCR分区：Q1

影响因子：4.3

年份：2023

卷号：16

期号：1

开始页：　

结束页：　

文献类型：Article

关键词：berberine hydrochloride; breast cancer; RRM2; epithelial-mesenchymal transition; bioinformatics

摘要："Berberine hydrochloride (BBR) could inhibit the proliferation, migration, and invasion of various cancer cells. As the only enzyme for the de novo synthesis of ribonucleotides, RRM2 is closely related to the development of tumorigenesis. However, not much is currently known about the functional roles of RRM2 in breast cancer (BRCA), and whether BBR regulates the migration and invasion of BRCA cells by regulating the expression of RRM2 remains to be determined. We study the effects of BBR on BRCA cell proliferation in vitro and tumorigenesis in vivo by using colony formation assays, EdU assays, and xenograft models. Transcriptome sequencing, the random forest algorithm, and KEGG analysis were utilized to explore the therapeutic target genes and relative pathways. The expression of RRM2 in BRCA patients was analyzed with The Cancer Genome Atlas (TCGA) dataset, the GEPIA website tool, the Gene Expression Omnibus (GEO) database, and the UALCAN database. The survival probability of BRCA patients could be predicted by survival curve and nomogram analysis. Molecular docking was used to explore the affinity between BBR and potential targets. Gain- and loss-of-function methods were employed to explore the biological process in RRM2 participants. We comprehensively investigated the pharmacological characteristics of BBR on BRCA cell lines and discovered that BBR could inhibit the proliferation of BRCA cells in vitro and in vivo. Combining transcriptome sequencing and KEGG analysis, we found that BBR mainly affected the biological behavior of BRCA cells via HIF-1 alpha and AMPK signal pathways. Additionally, by using bioinformatics and molecular docking, we demonstrated that RRM2 plays an oncogenic role in BRCA samples and that it acts as the hub gene of BBR on BRCA cells. Knockdown and overexpression studies indicated that RRM2 promoted BRCA cell migration as well as invasion in vitro by affecting the epithelial-to-mesenchymal transition (EMT). Our study demonstrated the significance of BBR regulating HIF-1 alpha and AMPK signaling pathways in BRCA cells. Moreover, we revealed the carcinogenic role and potential mechanism of RRM2 as a core regulatory factor of BBR in BRCA in controlling BRCA invasion, migration, and EMT, suggesting that RRM2 may be a therapeutic target and prognostic biomarker for BRCA therapy."

基金机构：Key projects of Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area [KFKT2022002]; Technology Research Program of Chongqing Municipal Education Commission [KJZD-K201802701]

基金资助正文："This study was supported by the Key projects of Chongqing Key Laboratory of Development and Utilization of Genuine Medicinal Materials in Three Gorges Reservoir Area (KFKT2022002, to Jing Li) and the Technology Research Program of Chongqing Municipal Education Commission (No. KJZD-K201802701, to Dilong Chen)."