MicroRNA‑126‑3p inhibits the proliferation, migration, invasion, and angiogenesis of triple‑negative breast cancer cells by targeting RGS3

  • Authors:
    • Zhipeng Hong
    • Chengye Hong
    • Bo Ma
    • Qinglan Wang
    • Xi Zhang
    • Liangqiang Li
    • Chuan Wang
    • Debo Chen
  • View Affiliations

  • Published online on: July 26, 2019     https://doi.org/10.3892/or.2019.7251
  • Pages: 1569-1579
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

Triple‑negative breast cancer (TNBC) is characterized by fast progression with high potential for metastasis, and poor prognosis. The dysregulation of microRNAs (miRNAs) occurring in the initiation or progression of cancers often leads to aberrant gene expression. The aim of the present study was to explore the function of miR‑126 in TNBC cells. Expression levels of miR‑126‑3p were determined by quantitative real‑time PCR. Then, the effects of miR‑126‑3p on migration, proliferation, invasion, and angiogenesis were assessed through in vitro experiments including Cell Counting Kit‑8, colony formation, Transwell invasion and vasculogenic mimicry formation assays. One of the target genes for miR‑126‑3p predicted by TargetScan was confirmed by luciferase activity assay. Results indicated that miR‑126‑3p expression was reduced in TNBC cell lines. Functional assays revealed that miR‑126‑3p overexpression inhibited cell proliferation, migration, invasion, colony formation capacity and vasculogenesis by 1.2‑, 1.8‑, 2.3‑, 2.0‑ and 3.3‑fold, respectively, compared to the miRNA‑negative control group of MDA‑MB‑231 cells (P<0.001, respectively). In addition, the regulator of G‑protein signaling 3 (RGS3) was hypothesized and validated as a direct target of miR‑126‑3p in TNBC. The proliferation, migration, invasion, colony formation capacity and vasculogenesis of MDA‑MB‑231 cells were significantly increased by 1.4‑, 2.0‑, 1.8‑, 1.4‑ and 3.2‑fold, respectively, in cells transfected with pcDNA3.0‑RGS3 compared to pcDNA3.0‑negative control groups (P<0.001, respectively). The influence of miR‑126‑3p expression was reversed by RGS3 restoration. Collectively, the present study revealed that miR‑126‑3p plays a role as a tumor suppressor in regulating TNBC cell activities by targeting RGS3, indicating that the miR‑126‑3p/RGS3 axis may be a potential treatment target.

References

1 

Siegel RL, Miller KD and Jemal A: Cancer statistics, 2017. CA Cancer J Clin. 67:7–30. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA and Jemal A: Global Cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 68:394–424. 2018. View Article : Google Scholar : PubMed/NCBI

3 

Yuan N, Meng M, Liu C, Feng L, Hou L, Ning Q, Xin G, Pei L, Gu S, Li X and Zhao X: Clinical characteristics and prognostic analysis of triple-negative breast cancer patients. Mol Clin Oncol. 2:245–251. 2014. View Article : Google Scholar : PubMed/NCBI

4 

Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y and Pietenpol JA: Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 121:2750̄–2767. 2011. View Article : Google Scholar

5 

Gerratana L, Fanotto V, Bonotto M, Bolzonello S, Minisini AM, Fasola G and Puglisi F: Pattern of metastasis and outcome in patients with breast cancer. Clin Exp Metastasis. 32:125–133. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Tsai CH, Chiu JH, Yang CW, Wang JY, Tsai YF, Tseng LM, Chen WS and Shyr YM: Molecular characteristics of recurrent triple-negative breast cancer. Mol Med Rep. 12:7326–7334. 2015. View Article : Google Scholar : PubMed/NCBI

7 

M Braden A, V Stankowski R, M Engel J and A Onitilo A: Breast cancer biomarkers: Risk assessment, diagnosis, prognosis, prediction of treatment efficacy and toxicity, and recurrence. Curr Pharm Des. 20:4879–4898. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Yang C, Hou C, Zhang H, Wang D, Ma Y, Zhang Y, Xu X, Bi Z and Geng S: miR-126 functions as a tumor suppressor in osteosarcoma by targeting Sox2. Int J Mol Sci. 15:423–437. 2013. View Article : Google Scholar : PubMed/NCBI

9 

Jones KB, Salah Z, Del Mare S, Galasso M, Gaudio E, Nuovo GJ, Lovat F, LeBlanc K, Palatini J, Randall RL, et al: miRNA signatures associate with pathogenesis and progression of osteosarcoma. Cancer Res. 72:1865–1877. 2012. View Article : Google Scholar : PubMed/NCBI

10 

Najafi Z, Sharifi M and Javadi G: Degradation of miR-21 induces apoptosis and inhibits cell proliferation in human hepatocellular carcinoma. Cancer Gene Ther. 22:530–535. 2015. View Article : Google Scholar : PubMed/NCBI

11 

Sandhu R, Rivenbark AG, Mackler RM, Livasy CA and Coleman WB: Dysregulation of microRNA expression drives aberrant DNA hypermethylation in basal-like breast cancer. Int J Oncol. 44:563–572. 2014. View Article : Google Scholar : PubMed/NCBI

12 

Zhu X, Li H, Long L, Hui L, Chen H, Wang X, Shen H and Xu W: miR-126 enhances the sensitivity of non-small cell lung cancer cells to anticancer agents by targeting vascular endothelial growth factor A. Acta Biochim Biophys Sin (Shanghai). 44:519–526. 2012. View Article : Google Scholar : PubMed/NCBI

13 

Yu Q, Liu SL, Wang H, Shi G, Yang P and Chen X: miR-126 suppresses the proliferation of cervical cancer cells and alters cell sensitivity to the chemotherapeutic drug bleomycin. Asian Pac J Cancer Prev. 14:6569–6572. 2014. View Article : Google Scholar : PubMed/NCBI

14 

Akao Y, Noguchi S, Iio A, Kojima K, Takagi T and Naoe T: Dysregulation of microRNA-34a expression causes drug-resistance to 5-FU in human colon cancer DLD-1 cells. Cancer Lett. 300:197–204. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Kuhnert F, Mancuso MR, Hampton J, Stankunas K, Asano T, Chen C and Kuo CJ: Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126. Development. 135:3989–3993. 2008. View Article : Google Scholar : PubMed/NCBI

16 

Liu W, Zhao ZY, Shi L and Yuan WD: Tissue microRNA-126 expression level predicts outcome in human osteosarcoma. Diagn Pathol. 10:1162015. View Article : Google Scholar : PubMed/NCBI

17 

Hansen TF, Nielsen BS, Jakobsen A and Sørensen FB: Intra-tumoural vessel area estimated by expression of epidermal growth factor-like domain 7 and microRNA-126 in primary tumours and metastases of patients with colorectal cancer: A descriptive study. J Transl Med. 13:102015. View Article : Google Scholar : PubMed/NCBI

18 

Fujii T, Shimada K, Tatsumi Y, Fujimoto K and Konishi N: Syndecan-1 responsive microRNA-126 and 149 regulate cell proliferation in prostate cancer. Biochem Biophys Res Commun. 456:183–189. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Liu LY, Wang W, Zhao LY, Guo B, Yang J, Zhao XG, Hou N, Ni L, Wang AY, Song TS, et al: MiR-126 inhibits growth of SGC-7901 cells by synergistically targeting the oncogenes PI3KR2 and Crk, and the tumor suppressor PLK2. Int J Oncol. 45:1257–1265. 2014. View Article : Google Scholar : PubMed/NCBI

20 

Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T, et al: Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 9:189–198. 2006. View Article : Google Scholar : PubMed/NCBI

21 

Maniotis AJ, Folberg R, Hess A, Seftor EA, Gardner LM, Pe'er J, Trent JM, Meltzer PS and Hendrix MJ: Vascular channel formation by human melanoma cells in vivo and in vitro: Vasculogenic mimicry. Am J Pathol. 155:739–752. 1999. View Article : Google Scholar : PubMed/NCBI

22 

Kirschmann DA, Seftor EA, Hardy KM, Seftor RE and Hendrix MJ: Molecular pathways: Vasculogenic mimicry in tumor cells: Diagnostic and therapeutic implications. Clin Cancer Res. 18:2726–2732. 2012. View Article : Google Scholar : PubMed/NCBI

23 

Meister J and Schmidt MHH: miR-126 and miR-126*: New players in cancer. ScientificWorldJournal. 10:2090–2100. 2010. View Article : Google Scholar : PubMed/NCBI

24 

Liu T, Sun B, Zhao X, Li Y, Gu Q, Dong X and Liu F: OCT4 expression and vasculogenic mimicry formation positively correlate with poor prognosis in human breast cancer. Int J Mol Sci. 15:19634–19649. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Liu T, Sun B, Zhao X, Gu Q, Dong X, Yao Z, Zhao N, Chi J, Liu N, Sun R and Ma Y: HER2/neu expression correlates with vasculogenic mimicry in invasive breast carcinoma. J Cell Mol Med. 17:116–122. 2013. View Article : Google Scholar : PubMed/NCBI

26 

Shirakawa K, Kobayashi H, Sobajima J, Hashimoto D, Shimizu A and Wakasugi H: Inflammatory breast cancer: Vasculogenic mimicry and its hemodynamics of an inflammatory breast cancer xenograft model. Breast Cancer Res. 5:136–139. 2003. View Article : Google Scholar : PubMed/NCBI

27 

Dulin NO, Pratt P, Tiruppathi C, Niu J, Voyno-Yasenetskaya T and Dunn MJ: Regulator of G protein signaling RGS3T is localized to the nucleus and induces apoptosis. J Biol Chem. 275:21317–21323. 2000. View Article : Google Scholar : PubMed/NCBI

28 

Eusemann TN, Willmroth F, Fiebich B, Biber K and van Calker D: Adenosine receptors differentially regulate the expression of regulators of G-protein signalling (RGS) 2, 3 and 4 in astrocyte-like cells. PLoS One. 10:e01349342015. View Article : Google Scholar : PubMed/NCBI

29 

Sethakorn N and Dulin NO: RGS expression in cancer: Oncomining the cancer microarray data. J Recept Signal Transduct Res. 33:166–171. 2013. View Article : Google Scholar : PubMed/NCBI

30 

Tatenhorst L, Senner V, Püttmann S and Paulus W: Regulators of G-protein signaling 3 and 4 (RGS3, RGS4) are associated with glioma cell motility. J Neuropathol Exp Neurol. 63:210–222. 2004. View Article : Google Scholar : PubMed/NCBI

31 

Feng R, Chen X, Yu Y, Su L, Yu B, Li J, Cai Q, Yan M, Liu B and Zhu Z: miR-126 functions as a tumour suppressor in human gastric cancer. Cancer Lett. 298:50–63. 2010. View Article : Google Scholar : PubMed/NCBI

32 

Wang J, Chen X, Li P, Su L, Yu B, Cai Q, Li J, Yu Y, Liu B and Zhu Z: CRKL promotes cell proliferation in gastric cancer and is negatively regulated by miR-126. Chem Biol Interact. 206:230–238. 2013. View Article : Google Scholar : PubMed/NCBI

33 

Wang J, Zhou Y, Fei X, Chen X and Zhu Z: Regulator of G-protein signaling 3 targeted by miR-126 correlates with poor prognosis in gastric cancer patients. Anticancer Drugs. 28:161–169. 2017. View Article : Google Scholar : PubMed/NCBI

34 

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

35 

Piasecka D, Braun M, Kordek R, Sadej R and Romanska H: MicroRNAs in regulation of triple-negative breast cancer progression. J Cancer Res Clin Oncol. 144:1401–1411. 2018. View Article : Google Scholar : PubMed/NCBI

36 

Zhang L, Xu Y, Jin X, Wang Z, Wu Y, Zhao D, Chen G, Li D, Wang X, Cao H, et al: A circulating miRNA signature as a diagnostic biomarker for non-invasive early detection of breast cancer. Breast Cancer Res Treat. 154:423–434. 2015. View Article : Google Scholar : PubMed/NCBI

37 

Wang B, Li J, Sun M, Sun L and Zhang X: miRNA expression in breast cancer varies with lymph node metastasis and other clinicopathologic features. IUBMB Life. 66:371–377. 2014. View Article : Google Scholar : PubMed/NCBI

38 

Gomes BC, Martins M, Lopes P, Morujão I, Oliveira M, Araújo A, Rueff J and Rodrigues AS: Prognostic value of microRNA-203a expression in breast cancer. Oncol Rep. 36:1748–1756. 2016. View Article : Google Scholar : PubMed/NCBI

39 

Wang Y, Zhang Z and Wang J: MicroRNA-384 inhibits the progression of breast cancer by targeting ACVR1. Oncol Rep. 39:2563–2574. 2018.PubMed/NCBI

40 

Zhang HD, Jiang LH, Hou JC, Zhou SY, Zhong SL, Zhu LP, Wang DD, Yang SJ, He YJ, Mao CF, et al: Circular RNA has_circ_0072995 promotes breast cancer cell migration and invasion through sponge for miR-30c-2-3p. Epigenomics. 10:1229–1242. 2018. View Article : Google Scholar : PubMed/NCBI

41 

Paszek S, Gabło N, Barnaś E, Szybka M, Morawiec J, Kołacińska A and Zawlik I: Dysregulation of microRNAs in triple-negative breast cancer. Ginekol Pol. 88:530–536. 2017. View Article : Google Scholar : PubMed/NCBI

42 

Otsubo T, Akiyama Y, Hashimoto Y, Shimada S, Goto K and Yuasa Y: MicroRNA-126 inhibits SOX2 expression and contributes to gastric carcinogenesis. PLoS One. 6:e166172011. View Article : Google Scholar : PubMed/NCBI

43 

Guo C, Sah JF, Beard L, Willson JK, Markowitz SD and Guda K: The noncoding RNA, miR-126, suppresses the growth of neoplastic cells by targeting phosphatidylinositol 3-kinase signaling and is frequently lost in colon cancers. Genes Chromosomes Cancer. 47:939–946. 2008. View Article : Google Scholar : PubMed/NCBI

44 

Zhang J, Du YY, Lin YF, Chen YT, Yang L, Wang HJ and Ma D: The cell growth suppressor, miR-126, targets IRS-1. Biochem Biophys Res Commun. 377:136–140. 2008. View Article : Google Scholar : PubMed/NCBI

45 

Chang YY, Kuo WH, Hung JH, Lee CY, Lee YH, Chang YC, Lin WC, Shen CY, Huang CS, Hseih FJ, et al: Deregulated microRNAs in triple-negative breast cancer revealed by deep sequencing. Mol Cancer. 14:362015. View Article : Google Scholar : PubMed/NCBI

46 

Liu Y, Cai Q, Bao PP, Su Y, Cai H, Wu J, Ye F, Guo X, Zheng W, Zheng Y and Shu XO: Tumor tissue microRNA expression in association with triple-negative breast cancer outcomes. Breast Cancer Res Treat. 152:183–191. 2015. View Article : Google Scholar : PubMed/NCBI

47 

Turashvili G, Lightbody ED, Tyryshkin K, SenGupta SK, Elliott BE, Madarnas Y, Ghaffari A, Day A and Nicol CJB: Novel prognostic and predictive microRNA targets for triple-negative breast cancer. FASEB J. 29:fj201800120R2018.

48 

Baldassari F, Zerbinati C, Galasso M, Corrà F, Minotti L, Agnoletto C, Previati M, Croce CM and Volinia S: Screen for microRNA and drug interactions in breast cancer cell lines points to miR-126 as a modulator of CDK4/6 and PIK3CA inhibitors. Front Genet. 9:1742018. View Article : Google Scholar : PubMed/NCBI

49 

Sun T, Zhao N, Zhao XL, Gu Q, Zhang SW, Che N, Wang XH, Du J, Liu YX and Sun BC: Expression and functional significance of Twist1 in hepatocellular carcinoma: Its role in vasculogenic mimicry. Hepatology. 51:545–556. 2010. View Article : Google Scholar : PubMed/NCBI

50 

Liu R, Yang K, Meng C, Zhang Z and Xu Y: Vasculogenic mimicry is a marker of poor prognosis in prostate cancer. Cancer Biol Ther. 13:527–533. 2012. View Article : Google Scholar : PubMed/NCBI

51 

Wang JY, Sun T, Zhao XL, Zhang SW, Zhang DF, Gu Q, Wang XH, Zhao N, Qie S and Sun BC: Functional significance of VEGF-a in human ovarian carcinoma: Role in vasculogenic mimicry. Cancer Biol Ther. 7:758–766. 2008. View Article : Google Scholar : PubMed/NCBI

52 

Li Y, Sun B, Zhao X, Zhang D, Wang X, Zhu D, Yang Z, Qiu Z and Ban X: Subpopulations of uPAR+ contribute to vasculogenic mimicry and metastasis in large cell lung cancer. Exp Mol Pathol. 98:136–144. 2015. View Article : Google Scholar : PubMed/NCBI

53 

Zhang D, Sun B, Zhao X, Ma Y, Ji R, Gu Q, Dong X, Li J, Liu F, Jia X, et al: Twist1 expression induced by sunitinib accelerates tumor cell vasculogenic mimicry by increasing the population of CD133+ cells in triple-negative breast cancer. Mol Cancer. 13:2072014. View Article : Google Scholar : PubMed/NCBI

54 

Wagenblast E, Soto M, Gutiérrez-Ángel S, Hartl CA, Gable AL, Maceli AR, Erard N, Williams AM, Kim SY, Dickopf S, et al: A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis. Nature. 520:358–362. 2015. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October 2019
Volume 42 Issue 4

Print ISSN: 1021-335X
Online ISSN:1791-2431

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Hong, Z., Hong, C., Ma, B., Wang, Q., Zhang, X., Li, L. ... Chen, D. (2019). MicroRNA‑126‑3p inhibits the proliferation, migration, invasion, and angiogenesis of triple‑negative breast cancer cells by targeting RGS3. Oncology Reports, 42, 1569-1579. https://doi.org/10.3892/or.2019.7251
MLA
Hong, Z., Hong, C., Ma, B., Wang, Q., Zhang, X., Li, L., Wang, C., Chen, D."MicroRNA‑126‑3p inhibits the proliferation, migration, invasion, and angiogenesis of triple‑negative breast cancer cells by targeting RGS3". Oncology Reports 42.4 (2019): 1569-1579.
Chicago
Hong, Z., Hong, C., Ma, B., Wang, Q., Zhang, X., Li, L., Wang, C., Chen, D."MicroRNA‑126‑3p inhibits the proliferation, migration, invasion, and angiogenesis of triple‑negative breast cancer cells by targeting RGS3". Oncology Reports 42, no. 4 (2019): 1569-1579. https://doi.org/10.3892/or.2019.7251