The miR 495-UBE2C-ABCG2/ERCC1 axis reverses cisplatin resistance by downregulating drug resistance genes in cisplatin-resistant non-small cell lung cancer cells.

Abstract

Cisplatin (DDP) resistance has become the leading cause of mortality in non-small cell lung cancer (NSCLC). miRNA dysregulation significantly contributes to tumor progression. In this study, we found that miR-495 was significantly downregulated in lung cancer tissue specimens. This study aimed to elucidate the functions, direct target genes, and molecular mechanisms of miR-495 in lung cancer. miR-495 downregulated its substrate UBE2C through direct interaction with UBE2C 3'- untranslated region. UBE2C is a proto-oncogene activated in lung cancer; however, its role in chemotherapeutic resistance is unclear. Herein, UBE2C expression levels were higher in DDP-resistant NSCLC cells; this was associated with the proliferation, invasion, and DDP resistance in induced cisplatin-resistant NSCLC cells. Furthermore, epithelial-mesenchymal transitions (EMT) contributed to DDP resistance. Moreover, UBE2C knockdown downregulated vimentin. In contrast, E-cadherin was upregulated. Importantly, miR-495 and UBE2C were associated with cisplatin resistance. We attempted to evaluate their effects on cell proliferation and cisplatin resistance. We also performed EMT, cell migration, and invasion assays in DDP-resistant NSCLC cells overexpressing miR-495 and under-expressing UBE2C. Furthermore, in silico assays coupled with western blotting and luciferase assays revealed that UBE2C directly binds to the 5'-UTR of the drug-resistance genes ABCG2 and ERCC1. Furthermore, miR-495 downregulated ABCG2 and ERCC1 via regulation of UBE2C. Together, the present results indicate that the miR495-UBE2C-ABCG2/ERCC1 axis reverses DDP resistance via downregulation of anti-drug genes and reducing EMT in DDP-resistant NSCLC cells.

• Authors: Jiwei Guo, Dan Jin, Yan Wu, Lijuan Yang, Jing Du, Kaikai Gong, Weiwei Chen, Juanjuan Dai, Shuang Miao, Sichuan Xi
• Journal: EBioMedicine (EBioMedicine) Vol. 35 Pg. 204-221 (09 2018) ISSN: 2352-3964 [Electronic] Netherlands
• PMID: 30146342 (Publication Type: Journal Article, Retracted Publication)
• Copyright: Copyright © 2018 The Author(s). Published by Elsevier B.V. All rights reserved.

Chemical References

• ABCG2 protein, human
• ATP Binding Cassette Transporter, Subfamily G, Member 2
• DNA-Binding Proteins
• MAS1 protein, human
• MIRN495 microRNA, human
• MicroRNAs
• Neoplasm Proteins
• Proto-Oncogene Mas
• UBE2C protein, human
• Ubiquitin-Conjugating Enzymes
• ERCC1 protein, human
• Endonucleases
• Cisplatin

Topics

• ATP Binding Cassette Transporter, Subfamily G, Member 2 (metabolism)
• Base Sequence
• Carcinoma, Non-Small-Cell Lung (drug therapy, genetics)
• Cell Line, Tumor
• Cell Movement (genetics)
• Cell Proliferation (drug effects)
• Cisplatin (pharmacology, therapeutic use)
• DNA-Binding Proteins (metabolism)
• Down-Regulation (drug effects, genetics)
• Drug Resistance, Neoplasm (drug effects, genetics)
• Endonucleases (metabolism)
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Lung Neoplasms (drug therapy, genetics)
• MicroRNAs (genetics, metabolism)
• Neoplasm Invasiveness
• Neoplasm Proteins (metabolism)
• Promoter Regions, Genetic (genetics)
• Protein Binding
• Proto-Oncogene Mas
• RNA Stability (genetics)
• Signal Transduction (genetics)
• Transcription, Genetic
• Ubiquitin-Conjugating Enzymes (metabolism)