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Cancer Cell International
Published in: Cancer Cell International 1/2018

Open Access 01-12-2018 | Primary research

Downregulation of hypermethylated in cancer-1 by miR-4532 promotes adriamycin resistance in breast cancer cells

Authors: Fan Feng, Xiaolan Zhu, Chunyan Wang, Liang Chen, Weiping Cao, Yueqin Liu, Qi Chen, Wenlin Xu

Published in: Cancer Cell International | Issue 1/2018

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Abstract

Background

MicroRNAs are small RNAs (~ 22 nt) that modulate the expression of thousands of genes in tumors and play important roles in the formation of multidrug resistance. In this study, we firstly investigated that miR-4532 involved in the multidrug resistance formation of breast cancer by targeting hypermethylated in cancer 1 (HIC-1), a tumor-suppressor gene.

Methods

To identify and characterize the possible miRNAs in regulating multidrug resistance, we employed the transcriptome sequencing approach to profile the changes in the expression of miRNAs and their target mRNAs were obtained by bioinformatics prediction. Then the molecular biology experiments were conducted to confirm miR-4532 involved in multidrug resistance formation of breast cancer.

Results

The luciferase reporter assay experiment was employed to confirm that HIC-1 was the target of miR-4532. Transfection with an miR-4532 mimic indicated miR-4532 mimic significantly increased breast cancer cell resistance to adriamycin. Cell proliferation and invasion assay experiments showed overexpression of HIC-1 inhibited the invasion and metastasis of breast cancer cells. Meanwhile, the interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3) signaling pathway was confirmed to be involving in multidrug resistance by western blotting experiments.

Conclusions

These results suggest that downregulation of hypermethylated in cancer-1 by miR-4532 could promote adriamycin resistance in breast cancer cells, in which the IL-6/STAT3 pathway was regulated by the HIC-1. This finding might contribute to new therapeutic target for reversal of tumor resistance.
Appendix
Available only for authorised users
Literature
1.
Li T, Mello-Thoms C, Brenna PC. Descriptive epidemiology of breast cancer in China: incidence, mortality, survival and prevalence. Breast Cancer Res Treat. 2016;159(3):395–406.CrossRefPubMed
2.
3.
Xu HX, Wu KJ, Tian YJ, Liu Q, Han N, Yuan X, Zhang L, Wu GS, Wu K. CD44 correlates with clinicopathological characteristics and is upregulated by EGFR in breast cancer. Int J Oncol. 2016;49:1343–50.CrossRefPubMedPubMedCentral
4.
Chewchuk S, Guo B, Parissenti AM. Alterations in estrogen signalling pathways upon acquisition of anthracycline resistance in breast tumor cells. PLoS ONE. 2017;12(2):e0172244.CrossRefPubMedPubMedCentral
5.
Kelly AA, Stephen GB, Andrea M, John FF, Rodney JS. Decreased expression of key tumor suppressor microRNAs is associated with lymph node metastases in triple negative breast cancer. BMC Cancer. 2014;14:51.CrossRef
6.
Veronika B, Michael ZM, Jonathan MG. Hypoxia represses microRNA biogenesis proteins in breast cancer cells. BMC Cancer. 2014;14:533.CrossRef
7.
Huang XJ, Xie XH, Wang H, Xiao XS, Yang L, Tian Z, Guo XF, Zhang LJ, Tang HL, Xie XM. PDL1 and LDHA act as ceRNAs in triple negative breast cancer by regulating miR-34a. J Exp Clin Cancer Res. 2017;36(1):129.CrossRefPubMedPubMedCentral
8.
He R, Liu P, Xie X, Zhou Y, Liao Q, Xiong W, Li X, Li G, Zeng Z, Tang H. circGFRA1 and GFRA1 act as ceRNAs in triple negative breast cancer by regulating miR-34a. J Exp Clin Cancer Res. 2017;36(1):145.CrossRefPubMedPubMedCentral
9.
10.
Li J, Lai YH, Ma JY, Liu Y, Bi J, Zhang LJ, Chen LZ, Yao C, Lv WM, Chang GQ, Wang SM, Oy M, Wang WJ. miR-17-5p suppresses cell proliferation and invasion by targeting ETV1 in triple-negative breast cancer. BMC cancer. 2017;17:745.CrossRefPubMedPubMedCentral
11.
Lai YH, Chen J, Wang XP, Wu YQ, Peng HT, Lin XH, Wang WJ. Collagen triple helix repeat containing-1 negatively regulated by microRNA-30c promotes cell proliferation and metastasis and indicates poor prognosis in breast cancer. J Exp Clin Cancer Res. 2017;36:92.CrossRefPubMedPubMedCentral
12.
Yang ZX, Zhang B, Wei J, Jiang GQ, Wu YL, Leng BJ, Xing CG. MiR-539 inhibits proliferation and migration of triple-negative breast cancer cells by down-regulating LAMA4 expression. Cancer Cell Int. 2018;18:16.CrossRefPubMedPubMedCentral
13.
Hamada S, Masamune A, Miura S, Satoh K, Shimosegawa T. MiR-365 induces gemcitabine resistance in pancreatic cancer cells by targeting the adaptor protein SHC1 and pro-apoptotic regulator BAX. Cell Signal. 2014;26:179–85.CrossRefPubMed
14.
15.
Wang Q, Cheng Y, Wang Y, Fan YB, Li C, Zhang Y, Wang YD, Dong Q, Ma YJ, Teng YE, Qu XJ, Liu YP. Tamoxifen reverses epithelial-mesenchymal transition by demethylating miR-200c in triple-negative breast cancer cells. BMC Cancer. 2017;17:492.CrossRefPubMedPubMedCentral
16.
Song Q, Chen Q, Wang Q, Yang L, Lv D, Jin G, Liu J, Li B, Fei X. ATF-3/miR-590-GOLPH3 signaling pathway regulates proliferation of breast cancer. BMC Cancer. 2018;18(1):255.CrossRefPubMed
17.
Pritchard CC, Cheng HH, Tewari M. MicroRNA profiling: approaches and considerations. Nat Rev Genet. 2015;13(5):358–69.CrossRef
18.
Xia W, Zhou JY, Luo HB, Liu YZ, Peng CC, Zheng WL, Ma WL. MicroRNA-32 promotes cell proliferation, migration and suppresses apoptosis in breast cancer cells by targeting FBXW7. Cancer Cell Int. 2017;17:14.CrossRefPubMedPubMedCentral
19.
Zhu H, Wu H, Liu X, Evans BR, Medina DJ, Liu CG, Yang JM. Role of MicroRNA miR-27a and miR-451 in the regulation of MDR1/P-glycoprotein expression in human cancer cells. Biochem Pharmacol. 2008;76:582–8.CrossRefPubMedPubMedCentral
20.
Boo L, Ho WY, Ali NM, Yeap SK, Ky H, Chan KG, Yin WF, Satharasinghe DA, Liew WC, Tan SW, Ong HK, Cheong SK. MiRNA transcriptome profiling of spheroid-enriched cells with cancer stem cell properties in human breast MCF-7 cell line. Int J Biol Sci. 2016;12(4):427–45.CrossRefPubMedPubMedCentral
21.
Nishida N, Nagasaka T, Nishimura T, Ikai I, Boland CR, Geol A. Aberrant methylation of multiple tumor suppressor genes in aging liver, chronic hepatitis, and hepatocellular carcinoma. Hepatology. 2008;47(3):908–18.CrossRefPubMedPubMedCentral
22.
Zeng S, Yang Y, Cheng X, Zhou B, Li P, Zhao Y, Kong X, Xu Y. HIC1 epigenetically represses CIITA transcription in B lymphocytes. Biochim Biophys Acta. 2016;1859(12):1481–9.CrossRefPubMed
23.
Zhao G, Qin Q, Zhang J, Liu Y, Deng S, Liu L, Wang B, Tian K, Wang C. Hypermethylation of HIC1 promoter and aberrant expression of HIC1/SIRT1 might contribute to the carcinogenesis of pancreatic cancer. Ann Surg Oncol. 2013;3:S301–11.CrossRef
24.
Cheng G, Sun X, Wang J, Xiao G, Wang X, Fan X, Zu L, Hao M, Qu Q, Mao Y, Xue Y, Wang J. HIC1 silencing in triple-negative breast cancer drives progression through misregulation of LCN2. Cancer Res. 2014;74(3):862–72.CrossRefPubMed
25.
Hu B, Zhang K, Li S, Li H, Yan Z, Huang L, Wu J, Han X, Jiang W, Mulatibieke T, Zheng L, Wan R, Wang X, Hu G. HIC1 attenuates invasion and metastasis by inhibiting the IL-6/STAT3 signalling pathway in human pancreatic cancer. Cancer Lett. 2016;376(2):387–98.CrossRefPubMed
26.
Wu W, Zhang L, Lin J, Huang H, Shi B, Lin X, Huang Z, Wang C, Qiu J, Wei X. Hypermethylation of the HIC1 promoter and aberrant expression of HIC1/SIRT1 contribute to the development of thyroid papillary carcinoma. Oncotarget. 2016;7(51):84416–27.PubMedPubMedCentral
27.
Dubuissez M, Faiderbe P, Pinte S, Dehennaut V, Rood BR, Leprince D. The Reelin receptors ApoER2 and VLDLR are direct target genes of HIC1 (Hypermethylated In Cancer 1). Biochem Biophys Res Commun. 2013;440(3):424–30.CrossRefPubMed
28.
Valenta T, Lukas J, Doubravska L, Fafilek B, Korinek V. HIC1 attenuates Wnt signaling by recruitment of TCF-4 and beta-catenin to the nuclear bodies. EMBO J. 2006;25(11):2326–37.CrossRefPubMedPubMedCentral
29.
Rood BR, Leprince D. Deciphering HIC1 control pathways to reveal new avenues in cancer therapeutics. Expert Opin Ther argets. 2013;17(7):811–27.CrossRef
30.
Markowski J, Sieroń AL, Kasperczyk K, Ciupińska-Kajor M, Auguściak-Duma A, Likus W. Expression of the tumor suppressor gene hypermethylated in cancer 1 in laryngeal carcinoma. Oncol Lett. 2015;9(5):2299–302.CrossRefPubMedPubMedCentral
31.
Kovalchuk O, Filkowski J, Meservy J, llnytskyy Y, Tryndyak VP, Chekhun VF, Pogribny IP. Involvement of microRNA-451 in resistance of the MCF-7 breast cancer cells to chemotherapeutic drug doxorubicin. Mol Cancer Ther. 2008;7(7):2152–9.CrossRefPubMed
32.
33.
Towbin HST, Gordon J. Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA. 1979;76:4350–4.CrossRefPubMed
34.
Ganoth A, Merimi KC, Peer D. Overcoming multidrug resistance with nanomedicines. Expert Opin Drug Deliv. 2015;12(2):223–38.CrossRefPubMed
35.
Png KJ, Halberg N, Yoshida M, Tavazoie SF. A microRNA regulon that mediates endothelial recruitment and metastasis by cancer cells. Nature. 2012;481:190–4.CrossRef
36.
Ninio-Many L, Grossman H, Levi M, Zilber S, Tsarfaty I, Shomron N, Tuvar A, Chuderland D, Stemmer SM, Ben-Aharon I, et al. MicroRNA miR-125a-3p modulates molecular pathway of motility and migration in prostate cancer cells. Oncoscience. 2014;1:250.CrossRefPubMedPubMedCentral
37.
Foveau B, Boulay G, Pinte S, Van Rechem C, Rood BR, Leprince D. The receptor tyrosine kinase EphA2 is a direct target gene of hypermethylated in cancer 1 (HIC1). J Biol Chem. 2012;287(8):5366–78.CrossRefPubMed
38.
Nicoll G, Crichton DN, McDowell HE, Kernohan N, Hupp TR, Thompson AM. Expression of the hypermethylated in cancer gene (HIC-1) is associated with good outcome in human breast cancer. Br J Cancer. 2001;85(12):1878–82.CrossRefPubMedPubMedCentral
39.
Hayashi M, Tokuchi Y, Hashimoto T, Hayashi S, Nishida K, Ishikawa Y, Nakagawa K, Tsuchiya S, Okumura S, Tsuchiya E. Reduced HIC-1 gene expression in non-small cell lung cancer and its clinical significance. Anticancer Res. 2001;21(1B):535–40.PubMed
40.
Boulay G, Malaquin N, Loison I, Foveau B, Van RC, Rood BR, Pourtier A, Leprince D. Loss of hypermethylated in cancer 1 (HIC1) in breast cancer cells contributes to stress-induced migration and invasion through β-2 adrenergic receptor (ADRB2) misregulation. J Biol Chem. 2012;287(8):5379–89.CrossRefPubMed
41.
Eggers H, Steffens S, Grosshennig A, Becker JU, Hennenlotter J, Stenzl A, Merseburger AS, Kuczyk MA, Serth J. Prognostic and diagnostic relevance of hypermethylated in cancer 1 (HIC1) CpG island methylation in renal cell carcinoma. Int J Oncol. 2012;40(5):1650–8.PubMed
42.
Zhao F, Pan S, Gu Y, Guo S, Dai Q, Yu Y, Zhang W. Reactivation of HIC-1 gene by saRNA inhibits clonogenicity and invasiveness in breast cancer cells. Oncol Lett. 2015;9(1):159–64.CrossRefPubMed
43.
Kumar S. Molecular cloning and expression of high GC-rich novel tumor suppressor gene HIC-1. Mol Biotechnol. 2014;56(11):1040–8.CrossRefPubMed
44.
Lin YW, Ren LL, Xiong H, Du W, Yu YN, Sun TT, Weng YR, Wang ZH, Wang JL, Wang YC, Cui Y, Sun DF, Han ZG, Shen N, Zou W, Xu J, Chen HY, Cao W, Hong J, Fang JY. Role of STAT3 and vitamin D receptor in EZH2-mediated invasion of human colorectal cancer. J Pathol. 2013;230(3):277–90.CrossRefPubMed
45.
Liu X, Wang J, Wang H, Yin G, Liu Y, Lei X, Xiang M. REG3A accelerates pancreatic cancer cell growth under IL-6-associated inflammatory condition: involvement of a REG3A-JAK2/STAT3 positive feedback loop. Cancer Lett. 2015;362(1):45–60.CrossRefPubMed
46.
Zhuang PY, Zhang KW, Wang JD, Zhou XP, Liu YB, Quan ZW, Shen J. Effect of TALEN-mediated IL-6 knockout on cell proliferation, apoptosis, invasion and anti-cancer therapy in hepatocellular carcinoma (HCC-LM3) cells. Oncotarget. 2017;8(44):77915–27.PubMedPubMedCentral
47.
Wang L, Cao L, Wang H, Liu B, Zhang Q, Meng Z, Wu X, Zhou Q, Xu K. Cancer-associated fibroblasts enhance metastatic potential of lung cancer cells through IL-6/STAT3 signaling pathway. Oncotarget. 2017;8(44):76116–28.PubMedPubMedCentral
Metadata
Title
Downregulation of hypermethylated in cancer-1 by miR-4532 promotes adriamycin resistance in breast cancer cells
Authors
Fan Feng
Xiaolan Zhu
Chunyan Wang
Liang Chen
Weiping Cao
Yueqin Liu
Qi Chen
Wenlin Xu
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2018
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-018-0616-x

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