Potential mechanism of cisplatin resistance in non-small cell lung cancer A549 cells analyzed by the whole-transcriptome_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

NI Yaojun ^1,2 , XU Zhongneng ¹ , CHEN Sheng ¹ ,  WANG Jun ²

1. Department of Cardiothoracic Surgery, Hospital Affiliated to Nanjing Medical University and Huai’an First People’s Hospital, Huai’an, 223001, Jiangsu, P.R.China;
2. Department of Cardiothoracic Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, P.R.China;

Corresponding author：

WANG Jun, Email: drwangjun@njmu.eud.cn

Keywords：

Non-small cell lung cancer; cisplatin resistance; whole transcriptome sequencing; ceRNA network

DOI：

10.7507/1007-4848.202003132

Video：

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Objective To reveal the potential mechanism of cisplatin resistance in non-small cell lung cancer A549 cells by comparing the expression profiles of wild-type A549 cells and cisplatin-resistant A549 cells (A549/DPP) through whole transcriptome sequencing analysis.Methods The cisplatin resistant A549 (A549/DDP) cell line was first established. Then, the whole-transcriptome analysis was conducted both on A549 and A549/DDP cells. Next, the differentially expressed RNAs of lncRNA-seq, circRNA-seq, and miRNA-seq data were identified, respectively, followed by functional enrichment analysis. Finally, a comprehensive analysis based on the whole transcriptome data was performed and the construction of the ceRNA network was carried out.Results A total of 4 517 lncRNA, 123 circRNA, and 145 miRNA were differentially expressed in A549/DDP cells compared with the A549 cell line. These different RNAs were significantly enriched in cancer-related pathways. The ceRNA network contained 12 miRNAs, 4 circRNAs, 23 lncRNAs, and 9 mRNA nodes, of which hsa-miR-125a-5p and hsa-miR-125b-5p were important miRNAs based on the topological analysis.Conclusion Tumor necrosis factor signaling pathway and p53 signaling pathway are involved in A549/DPP resistance. Hsa-miR-125a-5p and hsa-miR-125b-5p may be potential targets for reversing cisplatin resistance.

Citation： NI Yaojun, XU Zhongneng, CHEN Sheng, WANG Jun. Potential mechanism of cisplatin resistance in non-small cell lung cancer A549 cells analyzed by the whole-transcriptome. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2021, 28(1): 35-42. doi: 10.7507/1007-4848.202003132 Copy

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11.	Jiang HG, Chen P, Su JY, et al. Knockdown of REV3 synergizes with ATR inhibition to promote apoptosis induced by cisplatin in lung cancer cells. J Cell Physiol, 2017, 232(12): 3433-3443.
12.	Huang H, Chen AY, Ye X, et al. Myricetin inhibits proliferation of cisplatin-resistant cancer cells through a p53-dependent apoptotic pathway. Int J Oncol, 2015, 47(4): 1494-1502.
13.	王攀. 人胃癌顺铂耐药细胞系BGC-823/CDDP的建立及其耐药机制的初步研究. 重庆医科大学, 2005.
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29.	Jiang L, Huang Q, Zhang S, et al. Hsa-miR-125a-3p and hsa-miR-125a-5p are downregulated in non-small cell lung cancer and have inverse effects on invasion and migration of lung cancer cells. BMC Cancer, 2010, 10: 318.
30.	Liu J, Tang Q, Li S, et al. Inhibition of HAX-1 by miR-125a reverses cisplatin resistance in laryngeal cancer stem cells. Oncotarget, 2016, 7(52): 86446-86456.
31.	Jiang L, Huang Q, Chang J, et al. MicroRNA hsa-miR-125a-5p induces apoptosis by activating p53 in lung cancer cells. Exp Lung Res, 2011, 37(7): 387-398.
32.	Zhang Y, Gao JS, Tang X, et al. MicroRNA 125a and its regulation of the p53 tumor suppressor gene. FEBS Lett, 2009, 583(22): 3725-3730.
33.	Yang Q, Wang Y, Lu X, et al. MiR-125b regulates epithelial-mesenchymal transition via targeting sema4C in paclitaxel-resistant breast cancer cells. Oncotarget, 2015, 6(5): 3268-3279.
34.	Li Y, Chao Y, Fang Y, et al. MTA1 promotes the invasion and migration of non-small cell lung cancer cells by downregulating miR-125b. J Exp Clin Cancer Res, 2013, 32(1): 33.
35.	Kong F, Sun C, Wang Z, et al. MiR-125b confers resistance of ovarian cancer cells to cisplatin by targeting pro-apoptotic Bcl-2 antagonist killer 1. J Huazhong Univ Sci Technolog Med Sci, 2011, 31(4): 543.

1. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin, 2018, 68(6): 394-424.
2. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA Cancer J Clin, 2019, 69(1): 7-34.
3. Kelly D, Burke L, O'Brien C, et al. Co-occurrence of EGFR sensitising and resistance mutations at diagnosis in NSCLC. Ir J Med Sci, 2019: 405-408.
4. Liu N, Zhao R, Ma Y, et al. The development of epigenetics and related inhibitors for targeted drug design in cancer therapy. Curr Top Med Chem, 2018, 18(28): 2380-2394.
5. 《非小细胞肺癌血液EGFR基因突变检测中国专家共识》制订专家组. 非小细胞肺癌血液EGFR基因突变检测中国专家共识. 中华医学杂志, 2015, 95(46): 3721-3726.
6. Bylicki O, Paleiron N, Margery J, et al. Targeting the PD-1/PD-L1 immune checkpoint in EGFR-mutated or Alk-translocated non-small-cell lung cancer. Target Oncol, 2017, 12(5): 563-569.
7. Liang W, He Q, Chen Y, et al. Metastatic EML4-ALK fusion detected by circulating DNA genotyping in an EGFR-mutated NSCLC patient and successful management by adding ALK inhibitors: a case report. BMC Cancer, 2016, 16(1): 1-5.
8. Mense ES, Smit AAJ, Crul M, et al. The effect of rapid infusion of cisplatin on nephrotoxicity in patients with lung carcinoma. J Clin Pharm Ther, 2019, 44(2): 249-257.
9. Sun C, Zhu Y, Li X, et al. Scutellarin increases cisplatin-induced apoptosis and autophagy to overcome cisplatin resistance in non-small cell lung cancer via ERK/p53 and c-met/AKT signaling pathways. Front Pharmacol, 2018, 9: 92-98.
10. Zhou J, Hu Q, Zhang X, et al. Sensitivity to chemotherapeutics of NSCLC cells with acquired resistance to EGFR-TKIs is mediated by T790M mutation or epithelial-mesenchymal transition. Oncol Rep, 2018, 39(4): 1783-1792.
11. Jiang HG, Chen P, Su JY, et al. Knockdown of REV3 synergizes with ATR inhibition to promote apoptosis induced by cisplatin in lung cancer cells. J Cell Physiol, 2017, 232(12): 3433-3443.
12. Huang H, Chen AY, Ye X, et al. Myricetin inhibits proliferation of cisplatin-resistant cancer cells through a p53-dependent apoptotic pathway. Int J Oncol, 2015, 47(4): 1494-1502.
13. 王攀. 人胃癌顺铂耐药细胞系BGC-823/CDDP的建立及其耐药机制的初步研究. 重庆医科大学, 2005.
14. Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for illumina sequence data. Bioinformatics, 2014, 30(15): 2114-2120.
15. Yates A, Akanni W, Amode MR, et al. Ensembl 2016. Nucleic Acids Res, 2016, 44(D1): D710-D716.
16. Yu G, Wang LG, Han Y, et al. ClusterProfiler: An R package for comparing biological themes among gene clusters. OMICS, 2012, 16(5): 284-287.
17. Dong R, Ma XK, Chen LL, et al. Genome-wide annotation of circrnas and their alternative back-splicing/splicing with CIRCexplorer pipeline. Methods Mol Biol, 2019, 1870: 137-149.
18. Lun AT, Chen Y, Smyth GK. It's DE-licious: a recipe for differential expression analyses of rna-seq experiments using quasi-likelihood methods in edgeR. Methods Mol Biol, 2016, 1418: 391-416.
19. Langmead B, Salzberg SL. Fast gapped-read alignment with bowtie 2. Nat Methods, 2012, 9(4): 357-359.
20. Claudia C, Antonio C, Gloria B, et al. SpidermiR: An R/bioconductor package for integrative analysis with miRNA data. Int J Mol Sci, 2017, 18(2): 274-277.
21. Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res, 2003, 13(11): 2498-2504.
22. Shen M, Xu Z, Xu W, et al. Inhibition of ATM reverses EMT and decreases metastatic potential of cisplatin-resistant lung cancer cells through JAK/STAT3/PD-L1 pathway. J Exp Clin Cancer Res, 2019, 38(1): 149.
23. Barr MP, Gray SG, Hoffmann A, et al. Generation and characterisation of cisplatin-resistant non-small cell lung cancer cell lines displaying a stem-like signature. PLoS One, 2013, 8(1): e54193.
24. Cho SH, Kang IC. The inhibitory effect of cordycepin on the proliferation of cisplatin-resistant A549 lung cancer cells. Biochem Biophys Res Commun, 2018, 498(3): 431-436.
25. Duffy MJ, Synnott NC, Crown J. Mutant p53 as a target for cancer treatment. Eur J Cancer, 2017, 83: 258-265.
26. Wang S, Li W, Xue Z, et al. Molecular imaging of p53 signal pathway in lung cancer cell cycle arrest induced by cisplatin. Mol Carcinog, 2013, 52(11): 900-907.
27. Ali AY, Abedini MR, Tsang BK. The oncogenic phosphatase PPM1D confers cisplatin resistance in ovarian carcinoma cells by attenuating checkpoint kinase 1 and p53 activation. Oncogene, 2012, 31(17): 2175-2186.
28. An SH, Kang JH, Kim DH, et al. Vitamin C increases the apoptosis via up-regulation p53 during cisplatin treatment in human colon cancer cells. BMB Rep, 2011, 44(3): 211-216.
29. Jiang L, Huang Q, Zhang S, et al. Hsa-miR-125a-3p and hsa-miR-125a-5p are downregulated in non-small cell lung cancer and have inverse effects on invasion and migration of lung cancer cells. BMC Cancer, 2010, 10: 318.
30. Liu J, Tang Q, Li S, et al. Inhibition of HAX-1 by miR-125a reverses cisplatin resistance in laryngeal cancer stem cells. Oncotarget, 2016, 7(52): 86446-86456.
31. Jiang L, Huang Q, Chang J, et al. MicroRNA hsa-miR-125a-5p induces apoptosis by activating p53 in lung cancer cells. Exp Lung Res, 2011, 37(7): 387-398.
32. Zhang Y, Gao JS, Tang X, et al. MicroRNA 125a and its regulation of the p53 tumor suppressor gene. FEBS Lett, 2009, 583(22): 3725-3730.
33. Yang Q, Wang Y, Lu X, et al. MiR-125b regulates epithelial-mesenchymal transition via targeting sema4C in paclitaxel-resistant breast cancer cells. Oncotarget, 2015, 6(5): 3268-3279.
34. Li Y, Chao Y, Fang Y, et al. MTA1 promotes the invasion and migration of non-small cell lung cancer cells by downregulating miR-125b. J Exp Clin Cancer Res, 2013, 32(1): 33.
35. Kong F, Sun C, Wang Z, et al. MiR-125b confers resistance of ovarian cancer cells to cisplatin by targeting pro-apoptotic Bcl-2 antagonist killer 1. J Huazhong Univ Sci Technolog Med Sci, 2011, 31(4): 543.

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