Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2017

Open Access 01-12-2017 | Research article

Up-regulation of miR-146a increases the sensitivity of non-small cell lung cancer to DDP by downregulating cyclin J

Authors: Lin Shi, Zhaozhong Xu, Gang Wu, Xiaoting Chen, Yuanyuan Huang, Yanjing Wang, Weiqiang Jiang, Bin Ke

Published in: BMC Cancer | Issue 1/2017

Login to get access

Abstract

Background

Cisplatin (DDP)-based chemotherapy is the common first-line therapy for lung cancer. However, their efficacy is often limited by primary drug resistance and/or acquired drug resistance. The aim of this study was to investigate the function of miRNA-146a (miR-146a) in DDP-resistant non-small cell lung cancer (NSCLC), as well as the underlying mechanisms.

Methods

The effect of overexpression of miR-146a and/or knockdown of cyclin J (CCNJ) in A549/DDP and SPC-A1/DDP cells were investigated as follows. The cellular sensitivity to DDP, cell apoptosis, cell cycle and cell mobility were detected by CCK-8, flow cytometry, hoechst staining and cell invasion/migration assay, respectively. The effects of miR-146a overexpression in NSCLC resistant cells were further analyzed in a nude mouse xenograft model.

Results

Overexpression of miR-146a and/or knockdown of CCNJ significantly increased the sensitivity to DDP in A549/DDP and SPC-A1/DDP cells compared to NC group via arresting cell cycle, enhancing cell apoptosis, inhibiting cell viability and motility in vitro and in vivo. Furthermore, miR-146a could specially degrade the mRNA of CCNJ, as examined by dual luciferase report assay.

Conclusion

The study indicates a crucial role of miR-146a in the development of acquired drug resistance to DDP in NSCLC cells. Further understanding of miR-146a mediated crosstalk networks may promote the clinical use of miR-146a analogue in NSCLC therapy.
Literature
1.
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015;136(5):E359–86.CrossRefPubMed
2.
Shen DW, Pouliot LM, Hall MD, Gottesman MM. Cisplatin resistance: a cellular self-defense mechanism resulting from multiple epigenetic and genetic changes. Pharmacol Rev. 2012;64(3):706–21.CrossRefPubMedPubMedCentral
3.
Judson I, Kelland LR. New developments and approaches in the platinum arena. Drugs. 2000;59 Suppl 4:29–36. discussion 37–28.CrossRefPubMed
4.
5.
Oliver TG, Mercer KL, Sayles LC, Burke JR, Mendus D, Lovejoy KS, et al. Chronic cisplatin treatment promotes enhanced damage repair and tumor progression in a mouse model of lung cancer. Genes Dev. 2010;24(8):837–52.CrossRefPubMedPubMedCentral
6.
Rosell R, Lord RV, Taron M, Reguart N. DNA repair and cisplatin resistance in non-small-cell lung cancer. Lung Cancer. 2002;38(3):217–27.CrossRefPubMed
7.
Safaei R, Howell SB. Copper transporters regulate the cellular pharmacology and sensitivity to Pt drugs. Crit Rev Oncol Hematol. 2005;53(1):13–23.CrossRefPubMed
8.
Materon EM, Jimmy Huang PJ, Wong A, Pupim Ferreira AA, Sotomayor Mdel P, Liu J. Glutathione-s-transferase modified electrodes for detecting anticancer drugs. Biosens Bioelectron. 2014;58:232–6.CrossRefPubMed
9.
Kirschner K, Melton DW. Multiple roles of the ERCC1-XPF endonuclease in DNA repair and resistance to anticancer drugs. Anticancer Res. 2010;30(9):3223–32.PubMed
10.
11.
12.
13.
Cheng AM, Byrom MW, Shelton J, Ford LP. Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 2005;33(4):1290–7.CrossRefPubMedPubMedCentral
14.
Krol J, Loedige I, Filipowicz W. The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 2010;11(9):597–610.PubMed
15.
Xu P, Guo M, Hay BA. MicroRNAs and the regulation of cell death. Trends Genet. 2004;20(12):617–24.CrossRefPubMed
16.
Moitra K, Im K, Limpert K, Borsa A, Sawitzke J, Robey R, et al. Differential gene and microRNA expression between etoposide resistant and etoposide sensitive MCF7 breast cancer cell lines. PLoS One. 2012;7(9):e45268.CrossRefPubMedPubMedCentral
17.
Naidu S, Garofalo M. microRNAs: An Emerging Paradigm in Lung Cancer Chemoresistance. Front Med (Lausanne). 2015;2:77.
18.
Wu L, Pu X, Wang Q, Cao J, Xu F, Xu LI, et al. miR-96 induces cisplatin chemoresistance in non-small cell lung cancer cells by downregulating SAMD9. Oncol Lett. 2016;11(2):945–52.PubMed
19.
Li W, Wang W, Ding M, Zheng X, Ma S, Wang X. MiR-1244 sensitizes the resistance of non-small cell lung cancer A549 cell to cisplatin. Cancer Cell Int. 2016;16:30.CrossRefPubMedPubMedCentral
20.
Chen X, Jiang Y, Huang Z, Li D, Chen X, Cao M, et al. miRNA-378 reverses chemoresistance to cisplatin in lung adenocarcinoma cells by targeting secreted clusterin. Sci Rep. 2016;6:19455.CrossRefPubMedPubMedCentral
21.
Yang Z, Fang S, Di Y, Ying W, Tan Y, Gu W. Modulation of NF-kappaB/miR-21/PTEN pathway sensitizes non-small cell lung cancer to cisplatin. PLoS One. 2015;10(3):e0121547.CrossRefPubMedPubMedCentral
22.
Sui C, Meng F, Li Y, Jiang Y. miR-148b reverses cisplatin-resistance in non-small cell cancer cells via negatively regulating DNA (cytosine-5)-methyltransferase 1(DNMT1) expression. J Transl Med. 2015;13:132.CrossRefPubMedPubMedCentral
23.
Cao J, He Y, Liu HQ, Wang SB, Zhao BC, Cheng YS. MicroRNA 192 regulates chemo-resistance of lung adenocarcinoma for gemcitabine and cisplatin combined therapy by targeting Bcl-2. Int J Clin Exp Med. 2015;8(8):12397–403.PubMedPubMedCentral
24.
Zhao Z, Liu J, Wang C, Wang Y, Jiang Y, Guo M. MicroRNA-25 regulates small cell lung cancer cell development and cell cycle through cyclin E2. Int J Clin Exp Pathol. 2014;7(11):7726–34.PubMedPubMedCentral
25.
Shi Y, Lu J, Zhou J, Tan X, He Y, Ding J, et al. Long non-coding RNA Loc554202 regulates proliferation and migration in breast cancer cells. Biochem Biophys Res Commun. 2014;446(2):448–53.CrossRefPubMed
26.
Ning FL, Wang F, Li ML, Yu ZS, Hao YZ, Chen SS. MicroRNA-182 modulates chemosensitivity of human non-small cell lung cancer to cisplatin by targeting PDCD4. Diagn Pathol. 2014;9:143.CrossRefPubMedPubMedCentral
27.
Li J, Wang Y, Song Y, Fu Z, Yu W. miR-27a regulates cisplatin resistance and metastasis by targeting RKIP in human lung adenocarcinoma cells. Mol Cancer. 2014;13:193.CrossRefPubMedPubMedCentral
28.
Chen DQ, Pan BZ, Huang JY, Zhang K, Cui SY, De W, et al. HDAC 1/4-mediated silencing of microRNA-200b promotes chemoresistance in human lung adenocarcinoma cells. Oncotarget. 2014;5(10):3333–49.CrossRefPubMedPubMedCentral
29.
Feng B, Wang R, Song HZ, Chen LB. MicroRNA-200b reverses chemoresistance of docetaxel-resistant human lung adenocarcinoma cells by targeting E2F3. Cancer. 2012;118(13):3365–76.CrossRefPubMed
30.
Feng B, Wang R, Chen LB. MiR-100 resensitizes docetaxel-resistant human lung adenocarcinoma cells (SPC-A1) to docetaxel by targeting Plk1. Cancer Lett. 2012;317(2):184–91.CrossRefPubMed
31.
Wang X, Tang S, Le SY, Lu R, Rader JS, Meyers C, et al. Aberrant Expression of Oncogenic and Tumor-Suppressive MicroRNAs in Cervical Cancer Is Required for Cancer Cell Growth. PLoS One. 2008;3(7):e2557.
32.
He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, Volinia S, et al. The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci U S A. 2005;102(52):19075–80.CrossRefPubMedPubMedCentral
33.
Pacifico F, Crescenzi E, Mellone S, Iannetti A, Porrino N, Liguoro D, et al. Nuclear factor-{kappa}B contributes to anaplastic thyroid carcinomas through up-regulation of miR-146a. J Clin Endocrinol Metabol. 2010;95(3):1421–30.CrossRef
34.
Bhaumik D, Scott GK, Schokrpur S, Patil CK, Campisi J, Benz CC. Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. Oncogene. 2008;27(42):5643–7.CrossRefPubMedPubMedCentral
35.
Li Y, Vandenboom 2nd TG, Wang Z, Kong D, Ali S, Philip PA, et al. miR-146a suppresses invasion of pancreatic cancer cells. Cancer Res. 2010;70(4):1486–95.CrossRefPubMedPubMedCentral
36.
Wang G, Zhang M, Li Y, Zhou J, Chen L. Studying the effect of downregulating autophagy-related gene LC3 on TLR3 apoptotic pathway mediated by dsRNA in hepatocellular carcinoma cells. Cancer Res Treat. 2017;49(1):230–245.
37.
Chang A. Chemotherapy, chemoresistance and the changing treatment landscape for NSCLC. Lung Cancer. 2011;71(1):3–10.CrossRefPubMed
38.
Chang JC, Wooten EC, Tsimelzon A, Hilsenbeck SG, Gutierrez MC, Tham YL, et al. Patterns of resistance and incomplete response to docetaxel by gene expression profiling in breast cancer patients. J Clin Oncol. 2005;23(6):1169–77.CrossRefPubMed
39.
Kastl L, Brown I, Schofield AC. Altered DNA methylation is associated with docetaxel resistance in human breast cancer cells. Int J Oncol. 2010;36(5):1235–41.PubMed
40.
41.
Wang Q, Zhong M, Liu W, Li J, Huang J, Zheng L. Alterations of microRNAs in cisplatin-resistant human non-small cell lung cancer cells (A549/DDP). Exp Lung Res. 2011;37(7):427–34.CrossRefPubMed
42.
43.
Sun Q, Zhao X, Liu X, Wang Y, Huang J, Jiang B, et al. miR-146a functions as a tumor suppressor in prostate cancer by targeting Rac1. Prostate. 2014;74(16):1613–21.CrossRefPubMed
44.
Li H, Xie S, Liu M, Chen Z, Liu X, Wang L, et al. The clinical significance of downregulation of mir-124-3p, mir-146a-5p, mir-155-5p and mir-335-5p in gastric cancer tumorigenesis. Int J Oncol. 2014;45(1):197–208.PubMed
45.
Wu C, Cao Y, He Z, He J, Hu C, Duan H, et al. Serum levels of miR-19b and miR-146a as prognostic biomarkers for non-small cell lung cancer. Tohoku J Exp Med. 2014;232(2):85–95.CrossRefPubMed
46.
Huang S, He R, Rong M, Dang Y, Chen G. Synergistic effect of MiR-146a mimic and cetuximab on hepatocellular carcinoma cells. Biomed Res Int. 2014;2014:384121.PubMedPubMedCentral
47.
Xu B, Wang N, Wang X, Tong N, Shao N, Tao J, et al. MiR-146a suppresses tumor growth and progression by targeting EGFR pathway and in a p-ERK-dependent manner in castration-resistant prostate cancer. Prostate. 2012;72(11):1171–8.CrossRefPubMed
48.
Althoff F, Viktorinova I, Kastl J, Lehner CF. Drosophila Cyclin J is a mitotically stable Cdk1 partner without essential functions. Dev Biol. 2009;333(2):263–72.CrossRefPubMed
49.
Kolonin MG, Finley Jr RL. A role for cyclin J in the rapid nuclear division cycles of early Drosophila embryogenesis. Dev Biol. 2000;227(2):661–72.CrossRefPubMed
50.
Venturutti L, Cordo Russo RI, Rivas MA, Mercogliano MF, Izzo F, Oakley RH, et al. MiR-16 mediates trastuzumab and lapatinib response in ErbB-2-positive breast and gastric cancer via its novel targets CCNJ and FUBP1. Oncogene. 2016;35(48):6189–6202.
51.
Takano N, Hishida M, Inokawa Y, Hayashi M, Kanda M, Nishikawa Y, et al. CCNJ detected by triple combination array analysis as a tumor-related gene of hepatocellular carcinoma. Int J Oncol. 2015;46(5):1963–70.PubMed
52.
Harvey RC, Mullighan CG, Wang X, Dobbin KK, Davidson GS, Bedrick EJ, et al. Identification of novel cluster groups in pediatric high-risk B-precursor acute lymphoblastic leukemia with gene expression profiling: correlation with genome-wide DNA copy number alterations, clinical characteristics, and outcome. Blood. 2010;116(23):4874–84.CrossRefPubMedPubMedCentral
53.
Zhou W, Wang J, Man WY, Zhang QW, Xu WG. siRNA silencing EZH2 reverses cisplatin-resistance of human non-small cell lung and gastric cancer cells. Asian Pac J Cancer Prev. 2015;16(6):2425–30.CrossRefPubMed
54.
Li JH, Luo N, Zhong MZ, Xiao ZQ, Wang JX, Yao XY, et al. Inhibition of microRNA-196a might reverse cisplatin resistance of A549/DDP non-small-cell lung cancer cell line. Tumour Biol. 2016;37(2):2387–94.CrossRefPubMed
55.
Janikova M, Zizkova V, Skarda J, Kharaishvili G, Radova L, Kolar Z. Prognostic significance of miR-23b in combination with P-gp, MRP and LRP/MVP expression in non-small cell lung cancer. Neoplasma. 2016;63(4):576–87.CrossRefPubMed
Metadata
Title
Up-regulation of miR-146a increases the sensitivity of non-small cell lung cancer to DDP by downregulating cyclin J
Authors
Lin Shi
Zhaozhong Xu
Gang Wu
Xiaoting Chen
Yuanyuan Huang
Yanjing Wang
Weiqiang Jiang
Bin Ke
Publication date
01-12-2017
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2017
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-017-3132-9

Other articles of this Issue 1/2017

BMC Cancer 1/2017 Go to the issue

Study protocol

Multiparametric magnetic resonance imaging in mucosal primary head and neck cancer: a prospective imaging biomarker study

Research article

Evaluation of plasma brain-derived neurotrophic factor levels and self-perceived cognitive impairment post-chemotherapy: a longitudinal study

Study protocol

Communication about uncertainty and hope: A randomized controlled trial assessing the efficacy of a communication skills training program for physicians caring for cancer patients

Research article

Retrospective study of nonmucinous appendiceal adenocarcinomas: role of systemic chemotherapy and cytoreductive surgery

Research article

Rho kinase proteins display aberrant upregulation in vascular tumors and contribute to vascular tumor growth

Research article

Transcriptional changes induced by bevacizumab combination therapy in responding and non-responding recurrent glioblastoma patients
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits