期刊
CELLULAR SIGNALLING
卷 87, 期 -, 页码 -出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2021.110151
关键词
SNAI1; Breast cancer stem cells; Epithelial-to-mesenchymal transition; EMT-associated differential expressed genes; GM6001 (Ilomastat)
类别
资金
- DBT, Government of India, Cancer Pilot Project
- CSIR-JRF/SRF
- [6242-P65/RGCB/PMD/DBT/AMTD/2015]
The study identified the crucial role of SNAI1 in inducing the expression of differentially expressed genes in breast cancer cells, leading to increased migration, invasion, and in vitro tumorigenesis, comparable to TNBC. The activation of breast cancer stem cell (CSC) phenotypes mediated by SNAI1 was perturbed by inhibiting downstream target MMPs, highlighting the importance of MMPs in SNAI1-mediated EMT regulation.
Background: Triple-negative breast cancer (TNBC) tumors are composed of a heterogeneous population containing both cancer cells and cancer stem cells (CSCs). These CSCs are generated through an epithelial-to-mesenchymal transition (EMT), thus making it pertinent to identify the unique EMT-molecular targets that regulate this phenomenon. Methods and results: In the present study, we performed in silico analysis of microarray data from luminal, Her(2+), and TNBC cell lines and identified 15 relatively unexplored EMT-related differentially expressed genes (DEGs) along with the markedly high expression of EMT-transcription factor (EMT-TF), SNAI1. Interestingly, stable overexpression of SNAI1 in MCF-7 induced the expression of DEGs along with increased migration, invasion, and in vitro tumorigenesis that was comparable to TNBCs. Next, stable SNAI1 overexpression led to increased expression of DEGs that was reverted with SNAI1 silencing in both breast cancer cells and CSCs sorted from various TNBC cell lines. Higher fold enrichment of SNAI1 on E-boxes in the promoter regions suggested a positive regulation of ALCAM, MMP2, MMP13, MMP14, VCAN, ANKRD1, KRT16, CTGF, TGFRII beta, PROCR negative regulation of CDH1, DSP and DSC3B by SNAI1 leading to EMT. Furthermore, SNAI1-mediated increased migration, invasion, and tumorigenesis in these sorted cells led to the activation of signaling mediators, ERK1/2, STAT3, Src, and FAK. Finally, the SNAI1-mediated activation of breast CSC phenotypes was perturbed by inhibition of downstream target, MMPs using Ilomastat. Conclusion: Thus, the molecular investigation for the gene regulatory framework in the present study identified MMPs, a downstream effector in the SNAI1-mediated EMT regulation.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据