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Integrative gene expression profiling reveals that dysregulated triple microRNAs confer paclitaxel resistance in non-small cell lung cancer via co-targeting MAPT

Authors Cai Y, Jia R, Xiong H, Ren Q, Zuo W, Lin T, Lin R, Lei Y, Wang P, Dong H, Zhao H, Zhu L, Fu Y, Zeng Z, Zhang W, Wang S

Received 12 May 2019

Accepted for publication 22 July 2019

Published 5 August 2019 Volume 2019:11 Pages 7391—7404

DOI https://doi.org/10.2147/CMAR.S215427

Checked for plagiarism Yes

Review by Single-blind

Peer reviewers approved by Dr Amy Norman

Peer reviewer comments 2

Editor who approved publication: Dr Antonella D'Anneo


Yuanming Cai,1,* Ruxue Jia,2,3,* Haozhe Xiong,4 Qun Ren,2,3 Weimin Zuo,2,3 Tingting Lin,2,3 Rong Lin,2 Yan Lei,2 Ping Wang,2 Huiyue Dong,2 Hu Zhao,2,3 Ling Zhu,3 Yunfeng Fu,3 Zhiyong Zeng,5 Wei Zhang,6 Shuiliang Wang2,3

1Undergraduate Grade 2015, The 5th Clinical Medical School of Xinjiang Medical University, Urumchi, People’s Republic of China; 2Department of Urology, The 900th Hospital of the Joint Logistics Team, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 3Fujian Key Laboratory of Transplant Biology, Affiliated Dongfang Hospital, Xiamen University School of Medicine, Fuzhou, Fujian, People’s Republic of China; 4Undergraduate Grade 2017, Department of Bioengineering, College of Life Science, Fujian Normal University, Fuzhou, Fujian, People’s Republic of China; 5Department of Thoracic Surgery, The 900th Hospital of the Joint Logistics Team, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China; 6Department of Emergency, The 900th Hospital of the Joint Logistics Team, Fujian Medical University, Fuzhou, Fujian, People’s Republic of China

*These authors contributed equally to this work

Background: Paclitaxel has shown significant anti-tumor activity against non-small cell lung cancer (NSCLC); however, resistance to paclitaxel frequently occurs and represents a significant clinical problem and its underlying molecular mechanism remains elusive.
Methods: Long-term treatment of culture cell with paclitaxel was carried out to mimic the development of acquired drug resistance in NSCLC. Cell proliferation and clonogenic assay and apoptosis evaluation were carried out to determine the efficacy of paclitaxel on NSCLC cells. Western blot analyses were performed to determine the expression and activation of proteins. Apoptosis enzyme-linked immunosorbent assay was used to quantify cytoplasmic histone-associated DNA fragments. Microarray analyses were applied to explore both mRNA and miRNA expression profiles in NSCLC cells followed by integrative analysis. qRT-PCR was carried out to verify the differentially expressed mRNAs and miRNAs.
Results: The expression of 652 genes was shown to be changed at least 2-fold in paclitaxel-resistant NSCLC (H460_TaxR) cells with 511 upregulated and 141 downregulated as compared with that in parental H460 cells. The differentially expressed genes were functionally enriched in regulating the cell proliferation, cell death, and response to endogenous stimulus, and clustered in pathways such as cancer and signaling by the G protein-coupled receptor (GPCR). Moreover, 43 miRNAs were shown to be differentially expressed in H460_TaxR cells with 15 upregulated and 28 downregulated as compared with parental H460 cells. A total of 289 pairs of miRNA-potential target gene were revealed in H460_TaxR cells by bioinformatics analysis. Furthermore, integrative analysis of miRNAs and gene expression profiles revealed that dysregulated miR-362-3p, miR-766-3p, and miR-6507-3p might confer paclitaxel resistance in NSCLC via targeting MAPT simultaneously.
Conclusion: Our findings suggested that specific manipulation of MAPT-targeting miRNAs may be a novel strategy to overcome paclitaxel resistance in patients with NSCLC especially large-cell lung carcinoma.

Keywords: integrative analysis, non-small cell lung cancer, paclitaxel-resistance, gene expression profile, miRNAs

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