MiR-21 modulates the effect of EZH2 on the biological behavior of human lung cancer stem cells in vitro.

Hui Xia,Shaojun Li,Yingnan Zhao,Yunlong Zhao,Baoshi Zhang,Yang Liu,Wen Zhang

doi:10.18632/oncotarget.20006

Abstract

Non-small-cell lung cancer has a high mortality rate and poor prognosis. Therefore, novel therapeutic approaches are urgently needed to enhance patient survival rates. In this study, we investigated the effects of miR-21 and EZH2 on the biological behavior of human lung cancer stem cells in vitro. We found increased expression of EZH2 and miR-21 in LCSCs, and miR-21 overexpression increased EZH2 levels in LCSCs. In addition, EZH2 and miR-21 knockdown increased the sensitivity of LCSCs to chemo- and radiation therapy, and exogenous EZH2 expression rescued the effects of anti-miR-21. Cell proliferation was reduced by 39.2% and 69.7% in the presence of radio- or chemotherapy combined with anti-miR-21 transfection, respectively. The downstream molecules included Cdc2, cyclin B1, and Bcl-2, which are involved in the regulation of cell cycle and apoptosis and which could themselves be reduced or enhanced by changes in miR-21 and EZH2 levels in LCSCs. This study demonstrates the direct relationship between miR-21 and EZH2 which was increased by 43% after the application of the miR-21 mimic. Above data indicates that these two molecules can influence the biological behavior of LCSCs by altering their corresponding targets. Our findings support the potential roles of miR-21 and EZH2 in improving the therapeutic efficacy of clinical lung cancer treatments.

Highlights

Lung cancer, the leading cause of cancer-related mortality worldwide, has a high mortality rate and poor prognosis— non-small-cell lung cancer (NSCLC), which accounts for approximately 80% of all lung cancers and has a 5-year overall survival rate of < 15% [1, 2]
Our results demonstrate that down regulation of cell division cycle 2 (Cdc2), cyclin B1 expression correlates with altered cell cycle dynamics after changes in miR-21 or Enhancer of zeste homolog 2 (EZH2) levels, which might help to improve the therapeutic effects of chemotherapy or radiation therapy on Lung cancer stem cells (LCSCs)
Our data provide the following novel findings: (1) increased expression of EZH2 and miR-21 is observed in LCSCs; (2) miR-21 overexpression increases EZH2 levels in LCSCs; (3) knock down of EZH2 and miR-21 sensitizes LCSCs to chemo- and radiation therapy; (4) exogenous expression of EZH2 rescues the effects of anti-miR-21; (5) the downstream effectors, including Cdc2, cyclin B1, Bax and Bcl-2, which are involved in cell cycle progression and apoptosis, are up or down regulated by alterations in miR-21 and EZH2 levels in LCSCs

Summary

Introduction

The leading cause of cancer-related mortality worldwide, has a high mortality rate and poor prognosis— non-small-cell lung cancer (NSCLC), which accounts for approximately 80% of all lung cancers and has a 5-year overall survival rate of < 15% [1, 2]. Despite recent advances and developments in therapeutic strategies, including surgery, chemotherapy, and radiotherapy, poor survival remains an issue due to the high systemic toxicity and drug resistance that limit successful outcomes in most cases [5, 6]. Recent studies [11, 12] and our previous report [13] supported the role of side population (SP) cells, which can be isolated from human lung cancer cell lines and exhibit significant tumorinitiating activity and characteristic proteins, such as www.impactjournals.com/oncotarget

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