miR-506 regulates breast cancer cell metastasis by targeting IQGAP1

Sun,Guang; Liu,Yanxi; Wang,Keren; Xu,Zheli

doi:10.3892/ijo.2015.3161

miR-506 regulates breast cancer cell metastasis by targeting IQGAP1

Authors:
- Guang Sun
- Yanxi Liu
- Keren Wang
- Zheli Xu
View Affiliations

Affiliations: Breast Surgical Department of China-Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
Published online on: September 14, 2015 https://doi.org/10.3892/ijo.2015.3161
Pages: 1963-1970

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

MicroRNA (miRNA or miR)-506 is a novel miRNA related to the survival of breast cancer patients. However, the mechanism underlying miRNA-506 involvement in breast carcinogenesis remains unclear. In the present study, we found that miR-506 was downregulated in human breast malignant tissues and breast cancer cell lines by RT-qPCR analysis, and the expression level of miR-506 was decreased with the increasing of tumor stage. Subsequently, gain-of-function and loss-of-function experiments were performed in vitro, and the results from MTT assay, Transwell-Matrigel invasion assay and cell adhesion assay revealed that miR-506 suppresses cell proliferation, invasion and adhesion of breast cancer cells. Luciferase reporter assay revealed that IQ motif containing GTPase activating protein 1 (IQGAP1) is a direct target of miR-506. miR-506 represses the expression of IQGAP1 and its downstream extracellular signal regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathways, as demonstrated by the RT-qPCR and western blot analysis. Furthermore, we found that IQGAP1 rescues the effect of miR-506 on cell proliferation, invasion, adhesion, and the activation of ERK MAPK signaling. In conclusion, the present study is the first to provide evidence that miR-506 acts as a tumor suppressor, at least partially, by directly downregulating IQGAP1 in breast cancer cells. The miR-506/IQGAP1/ERK pathway may be a novel therapeutic target in breast cancer.

View Figures

View References

1	Badar F, Faruqui ZS, Ashraf A and Uddin N: Third world issues in breast cancer detection. J Pak Med Assoc. 57:137–140. 2007.PubMed/NCBI
2	Jamal S, Mamoon N, Moghal S, Mushtaq S and Luqman M: Carcinoma breast: A histopathological audit. J Coll Physicians Surg Pak. 16:117–119. 2006.PubMed/NCBI
3	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
4	Chaffer CL and Weinberg RA: A perspective on cancer cell metastasis. Science. 331:1559–1564. 2011. View Article : Google Scholar : PubMed/NCBI
5	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
6	Nelson KM and Weiss GJ: MicroRNAs and cancer: Past, present, and potential future. Mol Cancer Ther. 7:3655–3660. 2008. View Article : Google Scholar : PubMed/NCBI
7	Liu G, Sun Y, Ji P, Li X, Cogdell D, Yang D, Parker Kerrigan BC, Shmulevich I, Chen K, Sood AK, et al: MiR-506 suppresses proliferation and induces senescence by directly targeting the CDK4/6-FOXM1 axis in ovarian cancer. J Pathol. 233:308–318. 2014. View Article : Google Scholar : PubMed/NCBI
8	Arora H, Qureshi R and Park WY: miR-506 regulates epithelial mesenchymal transition in breast cancer cell lines. PLoS One. 8:e642732013. View Article : Google Scholar : PubMed/NCBI
9	Wen SY, Lin Y, Yu YQ, Cao SJ, Zhang R, Yang XM, Li J, Zhang YL, Wang YH, Ma MZ, et al: miR-506 acts as a tumor suppressor by directly targeting the hedgehog pathway transcription factor Gli3 in human cervical cancer. Oncogene. 34:717–725. 2015. View Article : Google Scholar
10	Streicher KL, Zhu W, Lehmann KP, Georgantas RW, Morehouse CA, Brohawn P, Carrasco RA, Xiao Z, Tice DA, Higgs BW, et al: A novel oncogenic role for the miRNA-506-514 cluster in initiating melanocyte transformation and promoting melanoma growth. Oncogene. 31:1558–1570. 2012. View Article : Google Scholar
11	Buffa FM, Camps C, Winchester L, Snell CE, Gee HE, Sheldon H, Taylor M, Harris AL and Ragoussis J: microRNA-associated progression pathways and potential therapeutic targets identified by integrated mRNA and microRNA expression profiling in breast cancer. Cancer Res. 71:5635–5645. 2011. View Article : Google Scholar : PubMed/NCBI
12	Zhao Y, Liu H, Li Y, Wu J, Greenlee AR, Yang C and Jiang Y: The role of miR-506 in transformed 16HBE cells induced by anti-benzo[a]pyrene-trans-7,8-dihydrodiol-9,10-epoxide. Toxicol Lett. 205:320–326. 2011. View Article : Google Scholar : PubMed/NCBI
13	Wang Y, Cui M, Sun BD, Liu FB, Zhang XD and Ye LH: MiR-506 suppresses proliferation of hepatoma cells through targeting YAP mRNA 3′UTR. Acta Pharmacol Sin. 35:1207–1214. 2014. View Article : Google Scholar : PubMed/NCBI
14	Weissbach L, Settleman J, Kalady MF, Snijders AJ, Murthy AE, Yan YX and Bernards A: Identification of a human rasGAP-related protein containing calmodulin-binding motifs. J Biol Chem. 269:20517–20521. 1994.PubMed/NCBI
15	Hart MJ, Callow MG, Souza B and Polakis P: IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs. EMBO J. 15:2997–3005. 1996.PubMed/NCBI
16	Noritake J, Watanabe T, Sato K, Wang S and Kaibuchi K: IQGAP1: A key regulator of adhesion and migration. J Cell Sci. 118:2085–2092. 2005. View Article : Google Scholar : PubMed/NCBI
17	White CD, Brown MD and Sacks DB: IQGAPs in cancer: A family of scaffold proteins underlying tumorigenesis. FEBS Lett. 583:1817–1824. 2009. View Article : Google Scholar : PubMed/NCBI
18	Johnson M, Sharma M and Henderson BR: IQGAP1 regulation and roles in cancer. Cell Signal. 21:1471–1478. 2009. View Article : Google Scholar : PubMed/NCBI
19	Lu SH, Jiang XJ, Xiao GL, Liu DY and Yuan XR: miR-124a restoration inhibits glioma cell proliferation and invasion by suppressing IQGAP1 and β-catenin. Oncol Rep. 32:2104–2110. 2014.PubMed/NCBI
20	Chen F, Zhu HH, Zhou LF, Wu SS, Wang J and Chen Z: IQGAP1 is overexpressed in hepatocellular carcinoma and promotes cell proliferation by Akt activation. Exp Mol Med. 42:477–483. 2010. View Article : Google Scholar : PubMed/NCBI
21	Nakamura H, Fujita K, Nakagawa H, Kishi F, Takeuchi A, Aute I and Kato H: Expression pattern of the scaffold protein IQGAP1 in lung cancer. Oncol Rep. 13:427–431. 2005.PubMed/NCBI
22	Wang XX, Li XZ, Zhai LQ, Liu ZR, Chen XJ and Pei Y: Overexpression of IQGAP1 in human pancreatic cancer. Hepatobiliary Pancreat Dis Int. 12:540–545. 2013. View Article : Google Scholar : PubMed/NCBI
23	Erdemir HH, Li Z and Sacks DB: IQGAP1 binds to estrogen receptor-α and modulates its function. J Biol Chem. 289:9100–9112. 2014. View Article : Google Scholar : PubMed/NCBI
24	Jadeski L, Mataraza JM, Jeong HW, Li Z and Sacks DB: IQGAP1 stimulates proliferation and enhances tumorigenesis of human breast epithelial cells. J Biol Chem. 283:1008–1017. 2008. View Article : Google Scholar
25	Brown MD and Sacks DB: IQGAP1 in cellular signaling: Bridging the GAP. Trends Cell Biol. 16:242–249. 2006. View Article : Google Scholar : PubMed/NCBI
26	Ren JG, Li Z and Sacks DB: IQGAP1 modulates activation of B-Raf. Proc Natl Acad Sci USA. 104:10465–10469. 2007. View Article : Google Scholar : PubMed/NCBI
27	Schaeffer HJ and Weber MJ: Mitogen-activated protein kinases: Specific messages from ubiquitous messengers. Mol Cell Biol. 19:2435–2444. 1999.PubMed/NCBI
28	Roy M, Li Z and Sacks DB: IQGAP1 is a scaffold for mitogen-activated protein kinase signaling. Mol Cell Biol. 25:7940–7952. 2005. View Article : Google Scholar : PubMed/NCBI
29	Roy M, Li Z and Sacks DB: IQGAP1 binds ERK2 and modulates its activity. J Biol Chem. 279:17329–17337. 2004. View Article : Google Scholar : PubMed/NCBI
30	McCubrey JA, Steelman LS, Chappell WH, Abrams SL, Wong EW, Chang F, Lehmann B, Terrian DM, Milella M, Tafuri A, et al: Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta. 1773:1263–1284. 2007. View Article : Google Scholar