MicroRNA-34a targets epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs) and inhibits breast cancer cell migration and invasion
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Saber Imani1,2,*, Chunli Wei1,3,*, Jingliang Cheng1,*, Md. Asaduzzaman Khan1,4,*, Shangyi Fu5, Luquan Yang1, Mousumi Tania1,6, Xianqin Zhang1, Xiuli Xiao7, Xianning Zhang8, Junjiang Fu1,3
1Key Laboratory of Epigenetics and Oncology, Research Center for Precision Medicine, Southwest Medical University, Luzhou, Sichuan, China
2Chemical Injuries Research Center, Baqiyatallah Medical Sciences University (BMSU), Tehran, Iran
3State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau (SAR), China
4Faculty of Applied Sciences, Ton Duc Thang University, Ho Chi Minh City, Vietnam
5The Honors College, University of Houston, Houston, TX, USA
6Division of Computer Aided Drug Design, Red-Green Computing Centre, Dhaka, Bangladesh
7Pathology Department, Southwest Medical University, Luzhou, Sichuan, China
8Department of Cell Biology and Medical Genetics, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
*These authors have contributed equally to this work
Keywords: microRNA-34a, thymoquinone, epithelial-mesenchymal transition, metastasis, breast cancer
Received: December 27, 2016 Accepted: January 25, 2017 Published: February 09, 2017
MicroRNA-34a (miR-34a) plays an essential role against tumorigenesis and progression of cancer metastasis. Here, we analyzed the expression, targets and functional effects of miR-34a on epithelial to mesenchymal transition-inducing transcription factors (EMT-TFs), such as TWIST1, SLUG and ZEB1/2, and an EMT-inducing protein NOTCH1 in breast cancer (BC) cell migration and invasion and its correlation with tumorigenesis and clinical outcomes. Expression of miR-34a is downregulated in human metastatic breast cancers (MBC) compared to normal breast tissues and is negatively correlated with clinicopathological features of MBC patients. Ectopic expression of miR-34a in MBC cell-line BT-549 significantly inhibits cell migration and invasion, but exhibits no clear effect on BC cell growth. We found that miR-34a is able to inactivate EMT signaling pathway with mediatory of NOTCH1, TWIST1, and ZEB1 upon 3′-UTR activity in MBC cell lines, but has no inhibitory effects on SLUG and ZEB2. Furthermore, we investigated the synergistic effects of Thymoquinone (TQ) and miR-34a together on the expression of EMT-associated proteins. Results showed that co-delivery of miR-34a and TQ is able to inactivate EMT signaling pathway by directly targeting TWIST1 and ZEB1 in BT-549 cell line, indicating that they might be a promising therapeutic combination against breast cancer metastasis. Epigenetic inactivation of the EMT-TFs/miR-34a pathway can potentially alter the equilibrium of these regulations, facilitating EMT and metastasis in BC. Altogether, our findings suggest that miR-34a alone could serve as a potential therapeutic agent for MBC, and together with TQ, their therapeutic potential is synergistically enhanced.
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