MiRNA-15a Mediates Cell Cycle Arrest and Potentiates Apoptosis in Breast Cancer Cells by Targeting Synuclein-γ

  • Li, Ping (Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Xie, Xiao-Bing (Medical Laboratory Center, First Affiliated Hospital, Hunan University of Chinese Medicine) ;
  • Chen, Qian (Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine) ;
  • Pang, Guo-Lian (Department of Pathology, First People Hospital of Qujing) ;
  • Luo, Wan (Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Tu, Jian-Cheng (Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Zheng, Fang (Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Liu, Song-Mei (Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Han, Lu (Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University) ;
  • Zhang, Jian-Kun (Department of Pathology, First People Hospital of Qujing) ;
  • Luo, Xian-Yong (Department of Pathology, First People Hospital of Qujing) ;
  • Zhou, Xin (Center for Gene Diagnosis, Zhongnan Hospital of Wuhan University)
  • Published : 2014.08.30


Background: Recent studies have indicated that microRNA-15a (miR-15a) is dysregulated in breast cancer (BC). We aimed to evaluate the expression of miR-15a in BC tissues and corresponding para-carcinoma tissues. We also focused on effects of miR-15a on cellular behavior of MDA-MB-231 and expression of its target gene synuclein-${\gamma}$ (SNCG). Materials and Methods: The expression levels of miR-15a were analysed in BC formalin fixed paraffin embedded (FFPE) tissues by microarray and quantitative real-time PCR. CCK-8 assays, cell cycle and apoptosis assays were used to explore the potential functions of miR-15a in MDA-MB-231 human BC cells. A luciferase reporter assay confirmed direct targets. Results: Downregulation of miR-15a was detected in most primary BCs. Ectopic expression of miR-15a promoted proliferation and suppressed apoptosis in vivo. Further studies indicated that miR-15a may directly interact with the 3'-untranslated region (3'-UTR) of SNCG mRNA, downregulating its mRNA and protein expression levels. SNCG expression was negatively correlated with miR-15a expression. Conclusions: MiR-15a has a critical role in mediating cell cycle arrest and promoting cell apoptosis of BC, probably by directly targeting SNCG. Thus, it may be involved in development and progression of BC.


microRNA-15a;breast cancer;SNCG;cell cycle;apoptosis


  1. Ambros V (2001). MicroRNAs: tiny regulators with great potential. Cell, 107, 823-6.
  2. Bartel DP (2004). MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell, 116, 281-97.
  3. Cai CK, Zhao GY, Tian LY, et al (2012). miR-15a and miR-16-1 downregulate CCND1 and induce apoptosis and cell cycle arrest in osteosarcoma. Oncol Rep, 28, 1764-70.
  4. Chen C, Ridzon DA, Broomer AJ, et al (2005). Real-time quantification of microRNAs by stem-loop RT-PCR. Nucleic Acids Res, 33, 179.
  5. Chen Q, Xia HW, Ge XJ, et al (2013). Serum miR-19a predicts resistance to FOLFOX chemotherapy in advanced colorectal cancer cases. Asian Pac J Cancer Prev, 14, 7421-6.
  6. Cortez MA, Welsh JW, Calin GA (2012). Circulating microRNAs as noninvasive biomarkers in breast cancer. Recent Results Cancer Res, 195, 151-61.
  7. Ferlay J, Shin HR, Bray F, et al (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer, 127, 2893-917.
  8. Garzon R, Heaphy CE, Havelange V, et al (2009). MicroRNA 29b functions in acute myeloid leukemia. Blood, 114, 5331-41.
  9. Guo J, Shou C, Meng L, et al (2007). Neuronal protein synuclein gamma predicts poor clinical outcome in breast cancer. Int J Cancer, 121, 1296-305.
  10. Harquail J, Benzina S, Robichaud GA (2012). MicroRNAs and breast cancer malignancy: an overview of miRNA-regulated cancer processes leading to metastasis. Cancer Epidemiol Biomarkers Prev, 11, 269-80.
  11. Huang F, Liu C, Shi YH, et al (2013). MicroRNA-101 inhibits cell proliferation, invasion, and promotes apoptosis by regulating cyclooxygenase-2 in Hela cervical carcinoma cells. Asian Pac J Cancer Prev, 14, 5915-20.
  12. Jiang Y, Liu YE, Goldberg ID, et al (2004). A novel heat-shock protein-associated chaperone, stimulates ligand-dependent estrogen receptor $\alpha$ signaling and mammary tumorigenesis. Cancer Res, 64, 4539-46.
  13. Jiang Y, Liu YE, Lu A, et al (2003). Stimulation of estrogen receptor signaling by gamma synuclein. Cancer Res, 63, 3899-903.
  14. Lian J, Zhang X, Tian H, et al (2009). Altered microRNA expression in patients with non-obstructive zoospermia. Reprod Biol Endocrinol, 7, 13.
  15. Liu YE, Pu W, Jiang Y, et al (2007). Chaperoning of estrogen receptor and induction of mammary gland proliferation by neuronal protein synuclein gamma. Oncogene, 26, 2115-25.
  16. Luo Q, Li X, Li J, et al (2013). MiR-15a is underexpressed and inhibits the cell cycle by targeting CCNE1 in breast cancer. Int J Oncol, 43, 1212-8.
  17. Ng SB, Yan J, Huang G, et al (2011). Dysregulated microRNAs affect pathways and targets of biologic relevance in nasaltype natural killer/T-cell lymphoma. Blood, 118, 4919-29.
  18. Paik JH, Jang JY, Jeon YK, et al (2011). MicroRNA-146a Downregulates $NF{\kappa}B$ Activity via Targeting TRAF6 and Functions as a Tumor Suppressor Having Strong Prognostic Implications in NK/T Cell Lymphoma. Clin Cancer Res, 17, 4761-71.
  19. Qin XJ, Ling BX (2012). Proteomic studies in breast cancer (Review). Oncol Lett, 3, 735-43.
  20. Shenouda SK, Alahari SK (2009). MicroRNA function in cancer: oncogene or a tumor suppressor? Cancer Metastasis Rev, 28, 369-78.
  21. Thorsen SB, Obad S, Jensen NF, et al (2012). The therapeutic potential of microRNAs in cancer. Cancer J, 18, 275-84.
  22. Valencia-Sanchez MA, Liu J, Hannon GJ, et al (2006). Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev, 20, 515-24.
  23. Wang H, Tan G, Dong L, et al (2012). Circulating MiR-125b as a marker predicting chemoresistance in breast cancer. PLoS One, 7, 34210.
  24. Wei F, Xu J, Tang L, et al (2012). p27 (Kip1) V109G polymorphism and cancer risk: a systematic review and meta-analysis. Cancer Biother Radiopharm, 27, 665-71.
  25. Wu K, Quan Z, Weng Z, et al (2007). Expression of neuronal protein synuclein gamma gene as a novel marker for breast cancer prognosis. Breast Cancer Res Treatment, 101, 259-67.
  26. Yamanaka Y, Tagawa H, Takahashi N, et al (2009). Aberrant overexpression of microRNAs activate AKT signaling via down-regulation of tumor suppressors in natural killer-cell lymphoma/leukemia. Blood, 114, 3265-75.
  27. Yu Q, Liu SL, Wang H, et al (2013). miR-126 Suppresses the proliferation of cervical cancer cells and alters cell sensitivity to the chemotherapeutic drug bleomycin. Asian Pac J Cancer Prev, 14, 6569-72.

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