MicroRNA‑124 suppresses cell proliferation and invasion of triple negative breast cancer cells by targeting STAT3

Shi,Pengfei; Chen,Cheng; Li,Xiang; Wei,Zhanjie; Liu,Zhimin; Liu,Yongjun

doi:10.3892/mmr.2019.10044

MicroRNA‑124 suppresses cell proliferation and invasion of triple negative breast cancer cells by targeting STAT3

Authors:
- Pengfei Shi
- Cheng Chen
- Xiang Li
- Zhanjie Wei
- Zhimin Liu
- Yongjun Liu
View Affiliations

Affiliations: Department of Thyroid and Breast Surgery, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, P.R. China, Department of General Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430000, P.R. China
Published online on: March 15, 2019 https://doi.org/10.3892/mmr.2019.10044
Pages: 3667-3675
Copyright: © Shi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

MicroRNAs (miRNAs) are pivotal regulators of the progression of carcinogenesis and negatively regulate the expression of tumour‑associated genes. Downregulation of miR‑124 expression has been demonstrated in various human cancer tissues, wherein miR‑124 serves as a tumour suppressor by targeting oncogenes. However, its function and underlying mechanism of action remain unclear in breast cancer. In the present study, the tissue‑specific expression of miR‑124 was detected in 10 paired triple‑negative breast cancer and normal tissues, and its inhibitory effects on cell growth and invasion were evaluated in vitro and in vivo. Bioinformatics analysis identified signal transducer and activator of transcription 3 (STAT3), a well‑known oncogene in breast cancer, as the potential target. Upregulation of miR‑124 expression decreased STAT3 mRNA and protein levels in breast cancer cells and the relative luciferase activity. Rescue experiments revealed that the transfection of a STAT3 expression plasmid reversed the inhibitory effect of miR‑124 on the proliferation and invasion of MDA‑MB‑468 cells. These data demonstrate that miR‑124 serves vital roles in the suppression of triple‑negative breast cancer via inhibition of cell proliferation and invasion through STAT3. These results highlight the potential role of miR‑124 as a diagnostic or therapeutic target in patients with breast cancer.

View Figures

View References

1	DeSantis C, Ma J, Bryan L and Jemal A: Breast cancer statistics, 2013. CA Cancer J Clin. 64:52–62. 2014. View Article : Google Scholar : PubMed/NCBI
2	Li Y, Cai B, Shen L, Dong Y, Lu Q, Sun S, Liu S, Ma S, Ma PX and Chen J: MiRNA-29b suppresses tumor growth through simultaneously inhibiting angiogenesis and tumorigenesis by targeting Akt3. Cancer Lett. 397:111–119. 2017. View Article : Google Scholar : PubMed/NCBI
3	Sun G, Sun L, Liu Y, Xing H and Wang K: Her-2 expression regulated by downregulation of miR-9 and which affects chemotherapeutic effect in breast cancer. Cancer Gene Ther. 24:194–202. 2017. View Article : Google Scholar : PubMed/NCBI
4	Liu Y, Li X, Zhu S, Zhang JG, Yang M, Qin Q, Deng SC, Wang B, Tian K, Liu L, et al: Ectopic expression of miR-494 inhibited the proliferation, invasion and chemoresistance of pancreatic cancer by regulating SIRT1 and c-Myc. Gene Ther. 22:729–738. 2015. View Article : Google Scholar : PubMed/NCBI
5	Li X, Deng SJ, Zhu S, Jin Y, Cui SP, Chen JY, Xiang C, Li QY, He C, Zhao SF, et al: Hypoxia-induced lncRNA-NUTF2P3-001 contributes to tumorigenesis of pancreatic cancer by derepressing the miR-3923/KRAS pathway. Oncotarget. 7:6000–6014. 2016.PubMed/NCBI
6	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004. View Article : Google Scholar : PubMed/NCBI
7	Winter J, Jung S, Keller S, Gregory RI and Diederichs S: Many roads to maturity: microRNA biogenesis pathways and their regulation. Nat Cell Biol. 11:228–234. 2009. View Article : Google Scholar : PubMed/NCBI
8	Wang B, Zou A, Ma L, Chen X, Wang L, Zeng X and Tan T: miR-455 inhibits breast cancer cell proliferation through targeting CDK14. Eur J Pharmacol. 807:138–143. 2017. View Article : Google Scholar : PubMed/NCBI
9	Li P, Xu T, Zhou X, Liao L, Pang G, Luo W, Han L, Zhang J, Luo X, Xie X and Zhu K: Downregulation of miRNA-141 in breast cancer cells is associated with cell migration and invasion: Involvement of ANP32E targeting. Cancer Med. 6:662–672. 2017. View Article : Google Scholar : PubMed/NCBI
10	Zhao M, Ang L, Huang J and Wang J: MicroRNAs regulate the epithelial-mesenchymal transition and influence breast cancer invasion and metastasis. Tumour Biol. 39:10104283176916822017. View Article : Google Scholar : PubMed/NCBI
11	Chen Z, Liu S, Tian L, Wu M, Ai F, Tang W, Zhao L, Ding J, Zhang L and Tang A: miR-124 and miR-506 inhibit colorectal cancer progression by targeting DNMT3B and DNMT1. Oncotarget. 6:38139–38150. 2015. View Article : Google Scholar : PubMed/NCBI
12	Sun Y, Ai X, Shen S and Lu S: NF-κB-mediated miR-124 suppresses metastasis of non-small-cell lung cancer by targeting MYO10. Oncotarget. 6:8244–8254. 2015. View Article : Google Scholar : PubMed/NCBI
13	Peng XH, Huang HR, Lu J, Liu X, Zhao FP, Zhang B, Lin SX, Wang L, Chen HH, Xu X, et al: MiR-124 suppresses tumor growth and metastasis by targeting Foxq1 in nasopharyngeal carcinoma. Mol Cancer. 13:1862014. View Article : Google Scholar : PubMed/NCBI
14	Cai WL, Huang WD, Li B, Chen TR, Li ZX, Zhao CL, Li HY, Wu YM, Yan WJ and Xiao JR: microRNA-124 inhibits bone metastasis of breast cancer by repressing Interleukin-11. Mol Cancer. 17:92018. View Article : Google Scholar : PubMed/NCBI
15	Du S, Li H, Sun X, Li D, Yang Y, Tao Z, Li Q and Liu K: MicroRNA-124 inhibits cell proliferation and migration by regulating SNAI2 in breast cancer. Oncol Rep. 36:3259–3266. 2016. View Article : Google Scholar : PubMed/NCBI
16	Wang Y, Chen L, Wu Z, Wang M, Jin F, Wang N, Hu X, Liu Z, Zhang CY, Zen K, et al: miR-124-3p functions as a tumor suppressor in breast cancer by targeting CBL. BMC Cancer. 16:8262016. View Article : Google Scholar : PubMed/NCBI
17	Feng T, Shao F, Wu Q, Zhang X, Xu D, Qian K, Xie Y, Wang S, Xu N, Wang Y and Qi C: miR-124 downregulation leads to breast cancer progression via LncRNA-MALAT1 regulation and CDK4/E2F1 signal activation. Oncotarget. 7:16205–16216. 2016.PubMed/NCBI
18	Liao XH, Xiang Y, Yu CX, Li JP, Li H, Nie Q, Hu P, Zhou J and Zhang TC: STAT3 is required for MiR-17-5p-mediated sensitization to chemotherapy-induced apoptosis in breast cancer cells. Oncotarget. 8:15763–15774. 2016.
19	Wang N, Wei L, Huang Y, Wu Y, Su M, Pang X, Wang N, Ji F, Zhong C, Chen T and Li B: miR520c blocks EMT progression of human breast cancer cells by repressing STAT3. Oncol Rep. 37:1537–1544. 2017. View Article : Google Scholar : PubMed/NCBI
20	Liu F, Zhang H and Song H: Upregulation of MEK5 by Stat3 promotes breast cancer cell invasion and metastasis. Oncol Rep. 37:83–90. 2017. View Article : Google Scholar : PubMed/NCBI
21	McDaniel JM, Varley KE, Gertz J, Savic DS, Roberts BS, Bailey SK, Shevde LA, Ramaker RC, Lasseigne BN, Kirby MK, et al: Genomic regulation of invasion by STAT3 in triple negative breast cancer. Oncotarget. 8:8226–8238. 2017. View Article : Google Scholar : PubMed/NCBI
22	Xiang Y, Liao XH, Yu CX, Yao A, Qin H, Li JP, Hu P, Li H, Guo W, Gu CJ and Zhang TC: MiR-93-5p inhibits the EMT of breast cancer cells via targeting MKL-1 and STAT3. Exp Cell Res. 357:135–144. 2017. View Article : Google Scholar : PubMed/NCBI
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
24	Kertesz M, Iovino N, Unnerstall U, Gaul U and Segal E: The role of site accessibility in microRNA target recognition. Nat Genet. 39:1278–1284. 2007. View Article : Google Scholar : PubMed/NCBI
25	Watson IR, Takahashi K, Futreal PA and Chin L: Emerging patterns of somatic mutations in cancer. Nat Rev Genet. 14:703–718. 2013. View Article : Google Scholar : PubMed/NCBI
26	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
27	Ilamathi M, Prabu PC, Ayyappa KA and Sivaramakrishnan V: Artesunate obliterates experimental hepatocellular carcinoma in rats through suppression of IL-6-JAK-STAT signalling. Biomed Pharmacother. 82:72–79. 2016. View Article : Google Scholar : PubMed/NCBI
28	Siveen KS, Sikka S, Surana R, Dai X, Zhang J, Kumar AP, Tan BK, Sethi G and Bishayee A: Targeting the STAT3 signaling pathway in cancer: Role of synthetic and natural inhibitors. Biochim Biophys Acta. 1845:136–154. 2014.PubMed/NCBI
29	Tkach M, Rosemblit C, Rivas MA, Proietti CJ, Díaz Flaqué MC, Mercogliano MF, Beguelin W, Maronna E, Guzmán P, Gercovich FG, et al: p42/p44 MAPK-mediated Stat3Ser727 phosphorylation is required for progestin-induced full activation of Stat3 and breast cancer growth. Endocr Relat Cancer. 20:197–212. 2013. View Article : Google Scholar : PubMed/NCBI
30	Banerjee K and Resat H: Constitutive activation of STAT3 in breast cancer cells: A review. Int J Cancer. 138:2570–2578. 2016. View Article : Google Scholar : PubMed/NCBI
31	Thakur R, Trivedi R, Rastogi N, Singh M and Mishra DP: Inhibition of STAT3, FAK and Src mediated signaling reduces cancer stem cell load, tumorigenic potential and metastasis in breast cancer. Sci Rep. 5:101942015. View Article : Google Scholar : PubMed/NCBI
32	Baek D, Villén J, Shin C, Camargo FD, Gygi SP and Bartel DP: The impact of microRNAs on protein output. Nature. 455:64–71. 2008. View Article : Google Scholar : PubMed/NCBI
33	Bird A: DNA methylation patterns and epigenetic memory. Genes Dev. 16:6–21. 2002. View Article : Google Scholar : PubMed/NCBI
34	Chen X and Huang L: LRSSLMDA: Laplacian regularized sparse subspace learning for MiRNA-disease association prediction. PLoS Comput Biol. 13:e10059122017. View Article : Google Scholar : PubMed/NCBI
35	Chen X, Yin J, Qu J and Huang L: MDHGI: Matrix decomposition and heterogeneous graph inference for miRNA-disease association prediction. PLoS Comput Biol. 14:e10064182018. View Article : Google Scholar : PubMed/NCBI
36	Chen X, Xie D, Wang L, Zhao Q, You ZH and Liu H: BNPMDA: Bipartite network projection for MiRNA-disease association prediction. Bioinformatics. 34:3178–3186. 2018. View Article : Google Scholar : PubMed/NCBI