1. Academic Validation
  2. Novel regulation of miR-34a-5p and HOTAIR by the combination of berberine and gefitinib leading to inhibition of EMT in human lung cancer

Novel regulation of miR-34a-5p and HOTAIR by the combination of berberine and gefitinib leading to inhibition of EMT in human lung cancer

  • J Cell Mol Med. 2020 May;24(10):5578-5592. doi: 10.1111/jcmm.15214.
Fang Zheng 1 Jing Li 1 2 ChangJu Ma 1 XiaoJuan Tang 1 Qing Tang 1 JingJing Wu 1 XiaoSu Chai 3 Jianhui Xie 4 Xiao-Bo Yang 4 Swei Sunny Hann 1
Affiliations

Affiliations

  • 1 Laboratory of Tumor Biology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 2 Department of Human Resource, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 3 Department of Medical Oncology, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
  • 4 Guangdong Provincial Key Laboratory of Clinical Research on Traditional Chinese Medicine Syndrome, The Second Clinical College of Guangzhou University of Chinese Medicine, Guangzhou, China.
Abstract

HOTAIR is an important carcinogenic lncRNA and involves in tumorigenesis, and invasion. MiR-34a-5p functions as a tumour suppressor. However, the underlying mechanism of HOTAIR regulation especially in association with miR-34a-5p in non-small-cell lung Cancer (NSCLC) has not been explored. Herein, we performed series of in vitro experiments, including viability, migration, invasion, Apoptosis and in vivo xenograft model, and identified that HOTAIR was remarkably elevated in NSCLC cells. Enforced HOTAIR expression promoted migration and invasion, while depleted HOTAIR diminished the ability of migration and invasion of NSCLC cells. We also observed that miR-34a-5p was dramatically inhibited in NSCLC cells and the binding correlation between HOTAIR and miR-34a-5p was confirmed by dual-luciferase reporter and RNA immunoprecipitation assays. We also showed that induction of miR-34a-5p and reduction of HOTAIR, and the interaction between miR-34a-5p and HOTAIR resulted in the suppression of epithelial-mesenchymal transition (EMT) as illustrated by induction of key epithelial markers E-cadherin expression, reduction of vimentin and EMT-inducing transcription factor snail. Excessive expression of snail resisted miR-34a-5p-inhibited cell growth. Snail binds to E-cadherin promoter and regulates E-cadherin expression. There was a synergy in combination of berberine and gefinitib in this process. Similar findings were also observed in a tumour xenograft model. Collectively, this is the first report demonstrating reciprocal interaction of miR-34a-5p- and HOTAIR-mediated regulation of snail resulting in inhibition of EMT process by the combination of berberine and gefitinib suggesting that regulation of miR-34a-5p- and HOTAIR-mediated inhibition of EMT may provide novel treatment paradigms for lung Cancer.

Keywords

E-cadherin; EMT; HOTAIR; NSCLC; Snail; miR-34a-5p.

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