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Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2017

Open Access 01-12-2017 | Research

iASPP induces EMT and cisplatin resistance in human cervical cancer through miR-20a-FBXL5/BTG3 signaling

Authors: Ying Xiong, Fei Sun, Peixin Dong, Hidemichi Watari, Junming Yue, Min-fei Yu, Chun-yan Lan, Yin Wang, Ze-biao Ma

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2017

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Abstract

Background

Epithelial–mesenchymal transition (EMT) and dysregulated microRNAs (miRNAs) have important roles in driving chemoresistance. We previously reported that iASPP is a key EMT inducer and could increase cisplatin resistance in cervical cancer (CC) cells. Herein, we investigate the downstream mechanisms through which iASPP contributes to EMT and cisplatin resistance in CC.

Methods

By using a lentiviral system, we investigated the effects of iASPP knockdown on CC cell growth and chemosensitivity of CC cells to cisplatin in vivo. We examined if miR-20a, which was up-regulated following iASPP overexpression, would influence metastatic phenotypes and cisplatin resistance in CC cells, and explored the possible molecular mechanisms involved.

Results

Knockdown of iASPP suppressed CC cell proliferation and sensitized CC cells to cisplatin in vivo. iASPP promotes miR-20a expression in a p53-dependent manner. Upregulation of miR-20a induced EMT and the recovery of CC cell invasion and cisplatin chemoresistance that was repressed by iASPP knockdown. We identified FBXL5 and BTG3 as two direct miR-20a targets. Silencing of FBXL5 and BTG3 restored cell invasion and cisplatin chemoresistance, which was suppressed by iASPP or miR-20a knockdown. Reduced FBXL5 and BTG3 expression was found in CC samples and associated with poor prognosis in CC patients.

Conclusions

iASPP promotes EMT and confers cisplatin resistance in CC via miR-20a-FBXL5/BTG3 signaling.
Appendix
Available only for authorised users
Literature
1.
2.
Forouzanfar MH, Foreman KJ, Delossantos AM, Lozano R, Lopez AD, Murray CJ, et al. Breast and cervical cancer in 187 countries between 1980 and 2010: a systematic analysis. Lancet. 2011;378:1461–84.CrossRefPubMed
3.
Pfaendler KS, Tewari KS. Changing paradigms in the systemic treatment of advanced cervical cancer. Am J Obstet Gynecol. 2016;214:22–30.CrossRefPubMed
4.
Tangjitgamol S, Katanyoo K, Laopaiboon M, Lumbiganon P, Manusirivithaya S, Supawattanabodee B. Adjuvant chemotherapy after concurrent chemoradiation for locally advanced cervical cancer. Cochrane Database Syst Rev. 2014;12, CD010401.
5.
Dasari S, Tchounwou PB. Cisplatin in cancer therapy: molecular mechanisms of action. Eur J Pharmacol. 2014;740:364–78.CrossRefPubMed
6.
Dong P, Ihira K, Hamada J, Watari H, Yamada T, Hosaka M, et al. Reactivating p53 functions by suppressing its novel inhibitor iASPP: a potential therapeutic opportunity in p53 wild-type tumors. Oncotarget. 2015;6:19968–75.CrossRefPubMedPubMedCentral
7.
Bergamaschi D, Samuels Y, O’Neil NJ, Trigiante G, Crook T, Hsieh JK, et al. iASPP oncoprotein is a key inhibitor of p53 conserved from worm to human. Nat Genet. 2003;33:162–7.CrossRefPubMed
8.
Bergamaschi D, Samuels Y, Jin B, Duraisingham S, Crook T, Lu X. ASPP1 and ASPP2: common activators of p53 family members. Mol Cell Biol. 2004;24:1341–50.CrossRefPubMedPubMedCentral
9.
10.
Jiang L, Siu MK, Wong OG, Tam KF, Lu X, Lam EW, et al. iASPP and chemoresistance in ovarian cancers: effects on paclitaxel mediated mitotic catastrophe. Clin Cancer Res. 2011;17:6924–33.CrossRefPubMed
11.
Liu H, Wang M, Diao S, Rao Q, Zhang X, Xing H, et al. siRNA-mediated downregulation of iASPP promotes apoptosis induced by etoposide and daunorubicin in leukemia cells expressing wild-type p53. Leuk Res. 2009;33:1243–8.CrossRefPubMed
12.
Li G, Wang R, Gao J, Deng K, Wei J, Wei Y. RNA interference mediated silencing of iASPP induces cell proliferation inhibition and G0/G1 cell cycle arrest in U251 human glioblastoma cells. Mol Cell Biochem. 2011;350:193–200.CrossRefPubMed
13.
Jia Y, Peng L, Rao Q, Xing H, Huai L, Yu P, et al. Oncogene iASPP enhances self-renewal of hematopoietic stem cells and facilitates their resistance to chemotherapy and irradiation. FASEB J. 2014;28:2816–27.CrossRefPubMed
14.
Deng J, Wang L, Chen H, Hao J, Ni J, Chang L, et al. Targeting epithelial-mesenchymal transition and cancer stem cells for chemoresistant ovarian cancer. Oncotarget. 2016;7:55771–88.PubMedPubMedCentral
15.
Dong P, Xiong Y, Watari H, Hanley SJ, Konno Y, Ihira K, et al. Suppression of iASPP-dependent aggressiveness in cervical cancer through reversal of methylation silencing of microRNA-124. Sci Rep. 2016;6:35480.CrossRefPubMedPubMedCentral
16.
Kyo S, Nakamura M, Kiyono T, Maida Y, Kanaya T, Tanaka M, et al. Successful immortalization of endometrial glandular cells with normal structural and functional characteristics. Am J Pathol. 2003;163:2259–69.CrossRefPubMedPubMedCentral
17.
Dong P, Xiong Y, Watari H, Hanley SJ, Konno Y, Ihira K, et al. MiR-137 and miR-34a directly target Snail and inhibit EMT, invasion and sphere-forming ability of ovarian cancer cells. J Exp Clin Cancer Res. 2016;35:132.CrossRefPubMedPubMedCentral
18.
Miao L, Song Z, Jin L, Zhu YM, Wen LP, Wu M. ARF antagonizes the ability of Miz-1 to inhibit p53-mediated transactivation. Oncogene. 2010;29:711–22.CrossRefPubMed
19.
Yan HL, Xue G, Mei Q, Wang YZ, Ding FX, Liu MF, et al. Repression of the miR-17-92 cluster by p53 has an important function in hypoxia-induced apoptosis. EMBO J. 2009;28:2719–32.CrossRefPubMedPubMedCentral
20.
Yamagishi M, Nakano K, Miyake A, Yamochi T, Kagami Y, Tsutsumi A, et al. Polycomb-mediated loss of miR-31 activates NIK-dependent NF-κB pathway in adult T cell leukemia and other cancers. Cancer Cell. 2012;21:121–35.CrossRefPubMed
21.
Konno Y, Dong P, Xiong Y, Suzuki F, Lu J, Cai M, et al. MicroRNA-101 targets EZH2, MCL-1 and FOS to suppress proliferation, invasion and stem cell-like phenotype of aggressive endometrial cancer cells. Oncotarget. 2014;5:6049–62.CrossRefPubMedPubMedCentral
22.
Rao E, Jiang C, Ji M, Huang X, Iqbal J, Lenz G, et al. The miRNA-17 ∼ 92 cluster mediates chemoresistance and enhances tumor growth in mantle cell lymphoma via PI3K/AKT pathway activation. Leukemia. 2012;26:1064–72.CrossRefPubMed
23.
Wong N, Wang X. miRDB: an online resource for microRNA target prediction and functional annotations. Nucleic Acids Res. 2015;43(Database issue):D146–52.CrossRefPubMed
24.
Wu W, Ding H, Cao J, Zhang W. FBXL5 inhibits metastasis of gastric cancer through suppressing Snail1. Cell Physiol Biochem. 2015;35:1764–72.CrossRefPubMed
25.
Wu WD, Wang M, Ding HH, Qiu ZJ. FBXL5 attenuates RhoGDI2-induced cisplatin resistance in gastric cancer cells. Eur Rev Med Pharmacol Sci. 2016;20:2551–7.PubMed
26.
Ren XL, Zhu XH, Li XM, Li YL, Wang JM, Wu PX, et al. Down-regulation of BTG3 promotes cell proliferation, migration and invasion and predicts survival in gastric cancer. J Cancer Res Clin Oncol. 2015;141:397–405.CrossRefPubMed
27.
Wan Q, Dingerdissen H, Fan Y, Gulzar N, Pan Y, Wu TJ, et al. BioXpress: an integrated RNA-seq-derived gene expression database for pan-cancer analysis. Database (Oxford). 2015;2015.
28.
Aguirre-Gamboa R, Gomez-Rueda H, Martínez-Ledesma E, Martínez-Torteya A, Chacolla-Huaringa R, Rodriguez-Barrientos A, et al. SurvExpress: an online biomarker validation tool and database for cancer gene expression data using survival analysis. PLoS One. 2013;8:e74250.CrossRefPubMedPubMedCentral
29.
Niero EL, Rocha-Sales B, Lauand C, Cortez BA, de Souza MM, Rezende-Teixeira P, et al. The multiple facets of drug resistance: one history, different approaches. J Exp Clin Cancer Res. 2014;33:37.CrossRefPubMedPubMedCentral
30.
Xu J, Liu D, Niu H, Zhu G, Xu Y, Ye D, et al. Resveratrol reverses Doxorubicin resistance by inhibiting epithelial-mesenchymal transition (EMT) through modulating PTEN/Akt signaling pathway in gastric cancer. J Exp Clin Cancer Res. 2017;36:19.CrossRefPubMedPubMedCentral
31.
Huang D, Duan H, Huang H, Tong X, Han Y, Ru G, et al. Cisplatin resistance in gastric cancer cells is associated with HER2 upregulation-induced epithelial-mesenchymal transition. Sci Rep. 2016;6:20502.CrossRefPubMedPubMedCentral
32.
Qureshi R, Arora H, Rizvi MA. EMT in cervical cancer: its role in tumour progression and response to therapy. Cancer Lett. 2015;356:321–31.CrossRefPubMed
33.
Cao L, Huang Q, He J, Lu J, Xiong Y. Elevated expression of iASPP correlates with poor prognosis and chemoresistance/radioresistance in FIGO Ib1-IIa squamous cell cervical cancer. Cell Tissue Res. 2013;352:361–9.CrossRefPubMed
34.
He L, Thomson JM, Hemann MT, Hernando-Monge E, Mu D, Goodson S, et al. A microRNA polycistron as a potential human oncogene. Nature. 2005;435:828–33.CrossRefPubMedPubMedCentral
35.
Castellano L, Giamas G, Jacob J, Coombes RC, Lucchesi W, Thiruchelvam P, et al. The estrogen receptor-alpha-induced microRNA signature regulates itself and its transcriptional response. Proc Natl Acad Sci U S A. 2009;106:15732–7.CrossRefPubMedPubMedCentral
36.
Lanza G, Ferracin M, Gafà R, Veronese A, Spizzo R, Pichiorri F, et al. mRNA/microRNA gene expression profile in microsatellite unstable colorectal cancer. Mol Cancer. 2007;6:54.CrossRefPubMedPubMedCentral
37.
Hayashita Y, Osada H, Tatematsu Y, Yamada H, Yanagisawa K, Tomida S, et al. A polycistronic microRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation. Cancer Res. 2005;65:9628–32.CrossRefPubMed
38.
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:e2557.CrossRefPubMedPubMedCentral
39.
40.
Xu T, Jing C, Shi Y, Miao R, Peng L, Kong S, et al. microRNA-20a enhances the epithelial-to-mesenchymal transition of colorectal cancer cells by modulating matrix metalloproteinases. Exp Ther Med. 2015;10:683–8.PubMedPubMedCentral
41.
Zhu M, Zhou X, Du Y, Huang Z, Zhu J, Xu J, et al. miR-20a induces cisplatin resistance of a human gastric cancer cell line via targeting CYLD. Mol Med Rep. 2016;14:1742–50.PubMed
42.
O’Donnell KA, Wentzel EA, Zeller KI, Dang CV, Mendell JT. c-Myc-regulated microRNAs modulate E2F1 expression. Nature. 2005;435:839–43.CrossRefPubMed
43.
Fuziwara CS, Kimura ET. High iodine blocks a Notch/miR-19 loop activated by the BRAF(V600E) oncoprotein and restores the response to TGFβ in thyroid follicular cells. Thyroid. 2014;24:453–62.CrossRefPubMedPubMedCentral
44.
Du Y, Liu P, Zang W, Wang Y, Chen X, Li M, et al. BTG3 upregulation induces cell apoptosis and suppresses invasion in esophageal adenocarcinoma. Mol Cell Biochem. 2015;404:31–8.CrossRefPubMed
Metadata
Title
iASPP induces EMT and cisplatin resistance in human cervical cancer through miR-20a-FBXL5/BTG3 signaling
Authors
Ying Xiong
Fei Sun
Peixin Dong
Hidemichi Watari
Junming Yue
Min-fei Yu
Chun-yan Lan
Yin Wang
Ze-biao Ma
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2017
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/s13046-017-0520-6

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