microRNA-200c downregulates XIAP expression to suppress proliferation and promote apoptosis of triple-negative breast cancer cells

Ren,Yi; Han,Xuedong; Yu,Kun; Sun,Su'an; Zhen,Linlin; Li,Zhi; Wang,Shui

doi:10.3892/mmr.2014.2222

microRNA-200c downregulates XIAP expression to suppress proliferation and promote apoptosis of triple-negative breast cancer cells

Authors:
- Yi Ren
- Xuedong Han
- Kun Yu
- Su'an Sun
- Linlin Zhen
- Zhi Li
- Shui Wang
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Affiliations: Department of Breast Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Department of Breast and Thyroid Surgery, Huai'an First People's Hospital, Huai'an, Jiangsu 223300, P.R. China, Department of Cardiology, Huai'an First People's Hospital, Huai'an, Jiangsu 223300, P.R. China, Department of Pathology, Huai'an First People's Hospital, Huai'an, Jiangsu 223300, P.R. China
Published online on: May 8, 2014 https://doi.org/10.3892/mmr.2014.2222
Pages: 315-321

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Abstract

Despite advances in the understanding of breast cancer, patients most commonly have a poor prognosis, particularly those with triple negative breast cancer (TNBC). microRNAs (miRNAs) are endogenous non‑coding small RNAs, and their aberrant expression is linked to numerous malignancies. In the present study, the expression levels of miR‑200c in patients with TNBC were analyzed and it was identified that miR‑200c was downregulated in TNBC samples, compared with that in normal adjacent tissues. miR‑200c was overexpressed in the TNBC cell line MDA‑MB‑231 and its functions were studied in vitro and in vivo. An in vitro study revealed that the overexpression of miR‑200c inhibited MDA‑MB‑231 cell proliferation and resulted in the induction of apoptosis. The in vivo data indicated that the overexpression of miR‑200c significantly inhibited tumor growth and increased the rate of apoptosis. Target prediction revealed that the X‑linked inhibitor of apoptosis (XIAP) had putative complementary sequences to miR‑200c, which was confirmed by a dual luciferase reporter assay. Western blot analysis further demonstrated that the expression of XIAP was markedly reduced and that caspase‑3 was highly activated by the overexpression of miR‑200c. These findings suggested that miR‑200c may function as a tumor suppressor gene in TNBC, at least partly via directly targeting XIAP, and may therefore act as a potential therapeutic target in the development of novel treatment strategies for TNBC.

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1	Berry DA, Cronin KA, Plevritis SK, et al; Cancer Intervention and Surveillance Modeling Network (CISNET) Collaborators. Effect of screening and adjuvant therapy on mortality from breast cancer. N Engl J Med. 353:1784–1792. 2005. View Article : Google Scholar : PubMed/NCBI
2	Toft DJ and Cryns VL: Minireview: Basal-like breast cancer: from molecular profiles to targeted therapies. Mol Endocrinol. 25:199–211. 2011. View Article : Google Scholar : PubMed/NCBI
3	Lee RC, Feinbaum RL and Ambros V: The C. elegans heterochronic gene lin-4 encodes small RNAs with antisense complementarity to lin-14. Cell. 75:843–854. 1993.
4	Bartel DP: MicroRNAs: target recognition and regulatory functions. Cell. 136:215–233. 2009. View Article : Google Scholar : PubMed/NCBI
5	Kwak PB, Iwasaki S and Tomari Y: The microRNA pathway and cancer. Cancer Sci. 101:2309–2315. 2010. View Article : Google Scholar : PubMed/NCBI
6	Ambros V: The functions of animal microRNAs. Nature. 431:350–355. 2004. View Article : Google Scholar : PubMed/NCBI
7	Alvarez-Garcia I and Miska EA: MicroRNA functions in animal development and human disease. Development. 132:4653–4662. 2005. View Article : Google Scholar : PubMed/NCBI
8	Katada T, Ishiguro H, Kuwabara Y, et al: microRNA expression profile in undifferentiated gastric cancer. Int J Oncol. 34:537–542. 2009.PubMed/NCBI
9	Croce CM: Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet. 10:704–714. 2009. View Article : Google Scholar : PubMed/NCBI
10	Yan LX, Wu QN, Zhang Y, et al: Knockdown of miR-21 in human breast cancer cell lines inhibits proliferation, in vitro migration and in vivo tumor growth. Breast Cancer Res. 13:R22011. View Article : Google Scholar : PubMed/NCBI
11	Li L, Xie X, Luo J, et al: Targeted expression of miR-34a using the T-VISA system suppresses breast cancer cell growth and invasion. Mol Ther. 20:2326–2334. 2012. View Article : Google Scholar : PubMed/NCBI
12	Wang R, Wang HB, Hao CJ, et al: miR-101 is involved in human breast carcinogenesis by targeting Stathmin1. PLoS One. 7:e461732012. View Article : Google Scholar : PubMed/NCBI
13	Wang B, Wang H and Yang Z: miR-122 inhibits cell proliferation and tumorigenesis of breast cancer by targeting IGF1R. PLoS One. 7:e470532012. View Article : Google Scholar : PubMed/NCBI
14	Sun Y, Wang M, Lin G, et al: Serum microRNA-155 as a potential biomarker to track disease in breast cancer. PLoS One. 7:e470032012. View Article : Google Scholar : PubMed/NCBI
15	Danson S, Dean E, Dive C and Ranson M: IAPs as a target for anticancer therapy. Curr Cancer Drug Targets. 7:785–794. 2007. View Article : Google Scholar : PubMed/NCBI
16	Stefani G and Slack FJ: Small non-coding RNAs in animal development. Nat Rev Mol Cell Bio. 9:219–230. 2008. View Article : Google Scholar : PubMed/NCBI
17	Yanaihara N, Caplen N, Bowman E, et al: Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 9:189–198. 2006. View Article : Google Scholar : PubMed/NCBI
18	He H, Jazdzewski K, Li W, et al: The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci USA. 102:19075–19080. 2005. View Article : Google Scholar : PubMed/NCBI
19	Cummins JM, He Y, Leary RJ, et al: The colorectal microRNAome. Proc Natl Acad Sci USA. 103:3687–3692. 2006. View Article : Google Scholar : PubMed/NCBI
20	Mattie MD, Benz CC, Bowers J, Sensinger K, et al: Optimized high-throughput microRNA expression profiling provides novel biomarker assessment of clinical prostate and breast cancer biopsies. Mol Cancer. 5:242006. View Article : Google Scholar
21	Iorio MV, Ferracin M, Liu CG, et al: MicroRNA gene expression deregulation in human breast cancer. Cancer Res. 65:7065–7070. 2005. View Article : Google Scholar : PubMed/NCBI
22	Blenkiron C, Goldstein LD, Thorne NP, et al: MicroRNA expression profiling of human breast cancer identifies new markers of tumor subtype. Genome Biol. 8:R2142007. View Article : Google Scholar : PubMed/NCBI
23	Wang C, Zheng X, Shen C and Shi Y: MicroRNA-203 suppresses cell proliferation and migration by targeting BIRC5 and LASP1 in human triple-negative breast cancer cells. J Exp Clin Cancer Res. 31:582012. View Article : Google Scholar : PubMed/NCBI
24	Castilla MÁ, Díaz-Martín J, Sarrió D, et al: MicroRNA-200 family modulation in distinct breast cancer phenotypes. PLoS One. 7:e477092012.PubMed/NCBI
25	Gregory PA, Bert AG, Paterson EL, et al: The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol. 10:593–601. 2008. View Article : Google Scholar : PubMed/NCBI
26	Hurteau GJ, Carlson JA, Roos E and Brock GJ: Stable expression of miR-200c alone is sufficient to regulate TCF8 (ZEB1) and restore E-cadherin expression. Cell Cycle. 8:2064–2069. 2009. View Article : Google Scholar : PubMed/NCBI
27	Wellner U, Schubert J, Burk UC, et al: The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol. 11:1487–1495. 2009. View Article : Google Scholar : PubMed/NCBI
28	Sun C, Cai M, Gunasekera AH, et al: NMR structure and mutagenesis of the inhibitor-of-apoptosis protein XIAP. Nature. 401:818–822. 1999. View Article : Google Scholar : PubMed/NCBI
29	Lima RT, Martins LM, Guimarães JE, Sambade C and Vasconcelos MH: Specific downregulation of bcl-2 and xIAP by RNAi enhances the effects of chemotherapeutic agents in MCF-7 human breast cancer cells. Cancer Gene Ther. 11:309–316. 2004. View Article : Google Scholar : PubMed/NCBI
30	Jiang C, Yi XP, Shen H and Li YX: Targeting X-linked inhibitor of apoptosis protein inhibits pancreatic cancer cell growth through p-Akt depletion. World J Gastroenterol. 18:2956–2965. 2012. View Article : Google Scholar : PubMed/NCBI
31	Cho EA, Oh JM, Kim SY, Kim Y and Juhnn YS: Heterotrimeric stimulatory GTP-binding proteins inhibit cisplatin-induced apoptosis by increasing X-linked inhibitor of apoptosis protein expression in cervical cancer cells. Cancer Sci. 102:837–844. 2011. View Article : Google Scholar
32	Liu S, Zhang P, Chen Z, Liu M, Li X and Tang H: MicroRNA-7 downregulates XIAP expression to suppress cell growth and promote apoptosis in cervical cancer cells. FEBS Lett. 587:2247–2253. 2013. View Article : Google Scholar : PubMed/NCBI
33	Xie Y, Tobin LA, Camps J, et al: MicroRNA-24 regulates XIAP to reduce the apoptosis threshold in cancer cells. Oncogene. 32:2442–2451. 2013. View Article : Google Scholar : PubMed/NCBI
34	Shin S, Moon KC, Park KU and Ha E: MicroRNA-513a-5p mediates TNF-α and LPS induced apoptosis via downregulation of X-linked inhibitor of apoptotic protein in endothelial cells. Biochimie. 94:1431–1436. 2012.PubMed/NCBI