Abstract
miR-374a has been reported to function as an oncogene during tumor pathogenesis. In this study, miR-374a is observed to reduce nasopharyngeal carcinoma (NPC) cell proliferation, migration, invasion, metastasis and cisplatin (DDP) resistance in vitro and in vivo. Mechanistic analyses indicate that miR-374a directly targets CCND1 to inactivate pPI3K/pAKT/c-JUN forming a negative feedback loop, as well as suppressing downstream signals related to cell cycle progression and epithelial−mesenchymal transition (EMT). Interestingly, we also observed that miR-374a direct targeting of CCND1 is modulated by tumor suppressor PDCD4 via suppressing pPI3K/pAKT/c-JUN signaling. In clinical specimens, miR-374a was positively and negatively correlated with expression of PDCD4 and CCND1, respectively. Our studies are the first to demonstrate that the miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop induced by PDCD4 supresses NPC cell growth, metastasis and chemotherapy resistance.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 50 print issues and online access
$259.00 per year
only $5.18 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lin KT, Yeh YM, Chuang CM, Yang SY, Chang JW, Sun SP et al. Glucocorticoids mediate induction of microRNA-708 to suppress ovarian cancer metastasis through targeting Rap1B. Nat Commun 2015; 6: 5917.
Bu P, Wang L, Chen KY, Rakhilin N, Sun J, Closa A et al. miR-1269 promotes metastasis and forms a positive feedback loop with TGF-β. Nat Commun 2015; 6: 6879.
Zhang P, Wang L, Rodriguez-Aguayo C, Yuan Y, Debeb BG, Chen D et al. miR-205 acts as a tumour radiosensitizer by targeting ZEB1 and Ubc13. Nat Commun 2014; 5: 5671.
Chen L, Gibbons DL, Goswami S, Cortez MA, Ahn YH, Byers LA et al. Metastasis is regulated via microRNA-200/ZEB1 axis control of tumour cell PD-L1 expression and intratumoral immunosuppression. Nat Commun 2014; 5: 5241.
Keklikoglou I, Hosaka K, Bender C, Bott A, Koerner C, Mitra D et al. MicroRNA-206 functions as a pleiotropic modulator of cell proliferation, invasion and lymphangiogenesis in pancreatic adenocarcinoma by targeting ANXA2 and KRAS genes. Oncogene 2015; 34: 4867–4878.
Que T, Song Y, Liu Z, Zheng S, Long H, Li Z et al. Decreased miRNA-637 is an unfavorable prognosis marker and promotes glioma cell growth, migration and invasion via direct targeting AKT1. Oncogene 2015; 34: 4952–4963.
Miko E, Czimmerer Z, Csanky E, Boros G, Buslig J, Dezso B et al. Differentially expressed microRNAs in small cell lung cancer. Exp Lung Res 2009; 35: 646–664.
Cai J, Guan H, Fang L, Yang Y, Zhu X, Yuan J et al. MicroRNA-374a activates Wnt/beta-catenin signaling to promote breast cancer metastasis. J Clin Invest 2013; 123: 566–579.
Wang Y, Xia H, Zhuang Z, Miao L, Chen X, Cai H . Axl-altered microRNAs regulate tumorigenicity and gefitinib resistance in lung cancer. Cell Death Dis 2014; 5: e1227.
Võsa U, Vooder T, Kolde R, Fischer K, Välk K, Tõnisson N et al. Identification of miR-374a as a prognostic marker for survival in patients with early-stage nonsmall cell lung cancer. Genes Chromosomes Cancer 2011; 50: 812–822.
Li JY, Zhang Y, Zhang WH, Jia S, Kang Y, Tian R . Effects of differential distribution of microvessel density, possibly regulated by miR-374a on breast cancer prognosis. Asian Pac J Cancer Prev 2013; 14: 1715–1720.
Yu X, Zhen Y, Yang H, Wang H, Zhou Y, Wang E et al. Loss of connective tissue growth factor as an unfavorable prognosis factor activates miR-18b by PI3K/AKT/C-JUN and C-Myc and promotes cell growth in nasopharyngeal carcinoma. Cell Death Dis 2013; 4: e634.
Zhen Y, Liu Z, Yang H, Yu X, Wu Q, Hua S et al. Tumor suppressor PDCD4 modulates miR-184-mediated direct suppression of C-MYC and BCL2 blocking cell growth and survival in nasopharyngeal carcinoma. Cell Death Dis 2013; 4: e872.
Wu A, Wu B, Guo J, Luo W, Wu D, Yang H et al. Elevated expression of CDK4 in lung cancer. J Transl Med 2011; 9: 38.
Cai LM, Lyu XM, Luo WR, Cui XF, Ye YF, Yuan CC et al. EBV-miR-BART7-3p promotes the EMT and metastasis of nasopharyngeal carcinoma cells by suppressing the tumor suppressor PTEN. Oncogene 2015; 34: 2156–2166.
Lu J, He ML, Wang L, Chen Y, Liu X, Dong Q et al. MiR-26a inhibits cell growth and tumorigenesis of nasopharyngeal carcinoma through repression of EZH2. Cancer Res 2011; 71: 225–233.
Zhao M, Luo R, Liu Y, Gao L, Fu Z, Fu Q et al. miR-3188 regulates nasopharyngeal carcinoma proliferation and chemosensitivity through a FOXO1-modulated positive feedback loop with mTOR-p-PI3K/AKT-c-JUN. Nat Commun 2016; 7: 11309.
Afonja O, Juste D, Das S, Matsuhashi S, Samuels HH . Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosis. Oncogene 2004; 23: 8135–8145.
Bitomsky N, Wethkamp N, Marikkannu R, Klempnauer KH . siRNA-mediated knockdown of Pdcd4 expression causes upregulation of p21(Waf1/Cip1) expression. Oncogene 2008; 27: 4820–4829.
Dweep H, Gretz N . miRWalk2.0: a comprehensive atlas of microRNA-target interactions. Nat Methods 2015; 12: 697.
Dweep H, Sticht C, Pandey P, Gretz N . miRWalk–database: prediction of possible miRNA binding sites by "walking" the genes of three genomes. J Biomed Inform 2011; 44: 839–847.
Ye Y, Jin L, Wilmott JS, Hu WL, Yosufi B, Thorne RF et al. PI(4,5)P2 5-phosphatase A regulates PI3K/AKT signalling and has a tumour suppressive role in human melanoma. Nat Commun 2013; 4: 1508.
Sorokin AV, MEMO1 Chen J. a new IRS1-interacting protein, induces epithelial-mesenchymal transition in mammary epithelial cells. Oncogene 2013; 32: 3130–3138.
Walsh AM, Kapoor GS, Buonato JM, Mathew LK, Bi Y, Davuluri RV et al. Sprouty2 Drives Drug Resistance and Proliferation in Glioblastoma. Mol Cancer Res 2015; 13: 1227–1237.
Tanaka K, Babic I, Nathanson D, Akhavan D, Guo D, Gini B et al. Oncogenic EGFR signaling activates an mTORC2-NF-kappaB pathway that promotes chemotherapy resistance. Cancer Discov 2011; 1: 524–538.
Zhou Y, Liang C, Xue F, Chen W, Zhi X, Feng X et al. Salinomycin decreases doxorubicin resistance in hepatocellular carcinoma cells by inhibiting the beta-catenin/TCF complex association via FOXO3a activation. Oncotarget 2015; 6: 10350–10365.
Liao H, Bai Y, Qiu S, Zheng L, Huang L, Liu T et al. MiR-203 downregulation is responsible for chemoresistance in human glioblastoma by promoting epithelial-mesenchymal transition via SNAI2. Oncotarget 2015; 6: 8914–8928.
Miow QH, Tan TZ, Ye J, Lau JA, Yokomizo T, Thiery JP et al. Epithelial-mesenchymal status renders differential responses to cisplatin in ovarian cancer. Oncogene 2015; 34: 1899–1907.
Lei K, Townsend DM, Tew KD . Protein cysteine sulfinic acid reductase (sulfiredoxin) as a regulator of cell proliferation and drug response. Oncogene 2008; 27: 4877–4887.
Jiang W, Kahn SM, Zhou P, Zhang YJ, Cacace AM, Infante AS et al. Overexpression of cyclin D1 in rat fibroblasts causes abnormalities in growth control, cell cycle progression and gene expression. Oncogene 1993; 8: 3447–3457.
Baldin V, Lukas J, Marcote MJ, Pagano M, Draetta G . Cyclin D1 is a nuclear protein required for cell cycle progression in G1. Genes Dev 1993; 7: 812–821.
Zhong Z, Yeow WS, Zou C, Wassell R, Wang C, Pestell RG et al. Cyclin D1/cyclin-dependent kinase 4 interacts with filamin A and affects the migration and invasion potential of breast cancer cells. Cancer Res 2010; 70: 2105–2114.
Ju X, Casimiro MC, Gormley M, Meng H, Jiao X, Katiyar S et al. Identification of a cyclin D1 network in prostate cancer that antagonizes epithelial-mesenchymal restraint. Cancer Res 2014; 74: 508–519.
Wang H, Wu Q, Liu Z, Luo X, Fan Y, Liu Y et al. Downregulation of FAP suppresses cell proliferation and metastasis through PTEN/PI3K/AKT and Ras-ERK signaling in oral squamous cell carcinoma. Cell Death Dis 2014; 5: e1155.
Larue L, Bellacosa A . Epithelial-mesenchymal transition in development and cancer: role of phosphatidylinositol 3' kinase/AKT pathways. Oncogene 2005; 24: 7443–7454.
Mihailovich M, Bremang M, Spadotto V, Musiani D, Vitale E, Varano G et al. miR-17-92 fine-tunes MYC expression and function to ensure optimal B cell lymphoma growth. Nat Commun 2015; 6: 8725.
Ebert MS, Sharp PA . Roles for microRNAs in conferring robustness to biological processes. Cell 2012; 149: 515–524.
Acknowledgements
This study was supported by National Nature Science Fund of China (No. 81372184 and No. 81401906) (http://www.nsfc.gov.cn), the Outstanding Young Teacher Training Project of Colleges and Universities in Guangdong Province (No. Yq2013136), Guangdong Province Education Foundation (No. 2014KTSCX107), and Yangcheng Scholar Research Projects from Universities of Guangzhou (No. 12A011D). We are also grateful to Dr Douglas E Linn (Brigham & Women’s Hospital, Boston, MA, USA) for critical reading of the manuscript.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies this paper on the Oncogene website
Supplementary information
Rights and permissions
About this article
Cite this article
Zhen, Y., Fang, W., Zhao, M. et al. miR-374a-CCND1-pPI3K/AKT-c-JUN feedback loop modulated by PDCD4 suppresses cell growth, metastasis, and sensitizes nasopharyngeal carcinoma to cisplatin. Oncogene 36, 275–285 (2017). https://doi.org/10.1038/onc.2016.201
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/onc.2016.201
This article is cited by
-
MicroRNA-181b-5p Facilitates Thyroid Cancer Growth via Targeting Programmed Cell Death 4
Molecular Biotechnology (2024)
-
MicroRNAs as the pivotal regulators of cisplatin resistance in head and neck cancers
Cancer Cell International (2023)
-
Precision medicine in nasopharyngeal carcinoma: comprehensive review of past, present, and future prospect
Journal of Translational Medicine (2023)
-
The role of long non-coding RNA HCG18 in cancer
Clinical and Translational Oncology (2022)
-
NAP1L1 interacts with hepatoma-derived growth factor to recruit c-Jun inducing breast cancer growth
Cancer Cell International (2021)