MiRNA-26a Contributes to the Acquisition of Malignant Behaviors of Doctaxel-Resistant Lung Adenocarcinoma Cells through Targeting EZH2.

Abstract

BACKGROUND/AIMS:

Accumulating evidence revealed that microRNAs (miRNAs) have been demonstrated as critical molecules in tumor development and progression. MiR-26a, located in a fragile chromosomal region associated with various human cancer, has been reported to be involved in regulating various cellular process, such as proliferation, apoptosis and invasion through targeting multiple oncogene. Docetaxel-mediated chemotherapy has been applied in improving the survival and prognosis of patients with advanced lung adenocarcinoma (LAD). However, chemoresistance remains a major impediment to clinical application of this agent. It has been presented that decreased miR-26a expression lead to cisplatin resistance and promoted growth and migration in human lung cancer. Enhancer of zeste homolog 2 (EZH2) is the target of miR-26a. The present study aimed to investigate the function of miR-26a/EZH2 in the acquisition of malignant behaviors of LAD.

METHODS:

MiR-26a and EZH2 expression levels in the dcetaxel-insensitive groups (n = 19) and the docetaxel-sensitive groups (n = 18) were assessed by qRT-PCR. Colony formation assay, flow cytometric analysis, wound healing assay, cell transwell assays and western blotting were performed to assess the effects of miR-26a on proliferation, apoptosis and epithelial-to-mesenchymal (EMT) phenotypes in docetaxel resistant LAD cells in vitro. Xenograft transplantation, immunohistochemistry, tunel assays and western blotting assays were employed to demonstrate the role of miR-26a in docetaxel resistant LAD cells in vivo. The expression level of EZH2 in docetaxel-resistant LAD cells and corresponding parental cells was detected by qRT-PCR and western blotting. The relationship between miR-26a and EZH2 was confirmed by luciferase reporter assay. And rescue assays were performed to further confirm that miRNA-26a contributes to the acquisition of malignant behaviors of docetaxel-resistant LAD cells through targeting EZH2.

RESULTS:

MiR-26a was significantly down-regulated in the dcetaxel-insensitive groups (n = 19) compared with the docetaxel-sensitive groups (n = 18) assessed by qRT-PCR. MiR-26a decreased the proliferation, increased the apoptosis rate and reversed EMT to MET of docetaxel-resistant LAD cells both in vivo and vitro. EZH2 was confirmed as target of miR-26a. Rescue assays further verified that the function of miR-26a exerts in docetaxel-resistant LAD cells is through targeting EZH2.

CONCLUSIONS:

Our data revealed that overexpression of miR-26a in docetaxel-resistant LAD cells could decrease the proliferation, increase the apoptosis rate and reverse EMT to MET of docetaxel-resistant LAD cells both in vivo and vitro and such function is partially exerted via downregulating EZH2. MiR-26a/EZH2 signal pathway makes contribute to the malignant phenotype of docetaxel-resistant of LAD cells which indicated that miR-26a exerts pivotal functions in the molecular etiology of chemoresistant lung adenocarcinoma.

• Authors: Jing Chen, Yuejuan Xu, Leilei Tao, Yan Pan, Kai Zhang, Rui Wang, Long-Bang Chen, Xiaoyuan Chu
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 41 Issue 2 Pg. 583-597 ( 2017) ISSN: 1421-9778 [Electronic] Germany
• PMID: 28214878 (Publication Type: Journal Article)
• Copyright: © 2017 The Author(s) Published by S. Karger AG, Basel.

Chemical References

• 3' Untranslated Regions
• Antagomirs
• Biomarkers, Tumor
• MicroRNAs
• RNA, Small Interfering
• Taxoids
• Docetaxel
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein

Topics

• 3' Untranslated Regions
• Adenocarcinoma (metabolism, pathology)
• Adenocarcinoma of Lung
• Antagomirs (metabolism)
• Apoptosis (drug effects)
• Base Sequence
• Biomarkers, Tumor (genetics, metabolism)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Docetaxel
• Drug Resistance, Neoplasm (drug effects)
• Enhancer of Zeste Homolog 2 Protein (antagonists & inhibitors, genetics, metabolism)
• Epithelial-Mesenchymal Transition
• Humans
• Lung Neoplasms (metabolism, pathology)
• MicroRNAs (antagonists & inhibitors, genetics, metabolism)
• Neoplasm Staging
• RNA Interference
• RNA, Small Interfering (metabolism)
• Sequence Alignment
• Taxoids (toxicity)