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Molecular and Cellular Biochemistry

, Volume 379, Issue 1–2, pp 69–75 | Cite as

miR-154 inhibits EMT by targeting HMGA2 in prostate cancer cells

  • Chen Zhu
  • Jie Li
  • Gong Cheng
  • Hai Zhou
  • Liangjun Tao
  • Hongzhou Cai
  • Pu Li
  • Qiang Cao
  • Xiaobing Ju
  • Xiaoxin Meng
  • Meilin Wang
  • Zhengdong Zhang
  • Chao Qin
  • Lixin Hua
  • Changjun YinEmail author
  • Pengfei ShaoEmail author
Article

Abstract

Epithelial–mesenchymal transition (EMT) is a crucial process that plays an important role in the invasion and metastasis of human cancers. High-mobility group AT-hook 2 (HMGA2) has been found to be involved in the EMT program, with its aberrant expression having been observed in a variety of malignant tumors. However, the mechanisms regulating HMGA2 expression remain incompletely understood. The objective of this study was to investigate whether mir-154 plays a critical role in EMT by regulating HMGA2. The expression levels of HMGA2 were examined in four samples of prostate cancer (PCa) tissue and adjacent non-tumorous tissue by Western blot analysis. The effects of forced expression of miR-154 or HMGA2 knockdown on PCa cells were evaluated by cell migration and invasion assays and Western blot analysis. HMGA2 was upregulated in the PCa tissue samples compared with the adjacent normal ones. Forced expression of miR-154 or HMGA2 knockdown significantly reduced the migratory and invasive capabilities of PCa cells in vitro and inhibited EMT gene expression, increased the levels of E-cadherin, an epithelial marker, and decreased the levels of vimentin, a mesenchymal marker. HMGA2 is a direct target gene of miR-154 by dual-luciferase reporter assay. Our findings suggest that miR-154 plays a role in regulating EMT by targeting HMGA2. Understanding the targets and regulating pathways of miR-154 may provide new insights into the underlying pathogenesis of PCa.

Keywords

Prostate cancer miR-154 EMT 

Notes

Acknowledgments

This work was supported by the Program for Development of Innovative Research Team in the First Affiliated Hospital of Nanjing Medical University, Provincial Initiative Program for Excellency Disciplines of Jiangsu Province, by the National Natural Science Foundation of China (Grant numbers 81171963, 81102089, and 81201998) and the Natural Science Foundation of Jiangsu Province (Grant number BK2011773).

Conflict of interest

The authors have no financial conflict of interest.

References

  1. 1.
    Yilmaz M, Christofori G (2009) EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev 28:15–33PubMedCrossRefGoogle Scholar
  2. 2.
    Liu YN, Yin JJ, Abou-Kheir W, Hynes PG, Casey OM, Fang L, Yi M, Stephens RM, Seng V, Sheppard-Tillman H, Martin P, Kelly K (2012) MiR-1 and miR-200 inhibit EMT via Slug-dependent and tumorigenesis via Slug-independent mechanisms. Oncogene 32(3):296–306PubMedCrossRefGoogle Scholar
  3. 3.
    Ozcan S (2009) MiR-30 family and EMT in human fetal pancreatic islets. Islets 1:283–285PubMedCrossRefGoogle Scholar
  4. 4.
    Bartel DP (2004) MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116:281–297PubMedCrossRefGoogle Scholar
  5. 5.
    Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59:225–249PubMedCrossRefGoogle Scholar
  6. 6.
    Porkka KP, Pfeiffer MJ, Waltering KK, Vessella RL, Tammela TL, Visakorpi T (2007) MicroRNA expression profiling in prostate cancer. Cancer Res 67:6130–6135PubMedCrossRefGoogle Scholar
  7. 7.
    Zhu C, Shao P, Bao M, Li P, Zhou H, Cai H, Cao Q, Tao L, Meng X, Ju X, Qin C, Li J, Yin C (2013) miR-154 inhibits prostate cancer cell proliferation by targeting CCND2. Urol Oncol. doi: 10.1016/j.urolonc.2012.11.013 Google Scholar
  8. 8.
    Chiappetta G, Avantaggiato V, Visconti R, Fedele M, Battista S, Trapasso F, Merciai BM, Fidanza V, Giancotti V, Santoro M, Simeone A, Fusco A (1996) High level expression of the HMGI (Y) gene during embryonic development. Oncogene 13:2439–2446PubMedGoogle Scholar
  9. 9.
    Rogalla P, Drechsler K, Frey G, Hennig Y, Helmke B, Bonk U, Bullerdiek J (1996) HMGI-C expression patterns in human tissues. Implications for the genesis of frequent mesenchymal tumors. Am J Pathol 149:775–779PubMedGoogle Scholar
  10. 10.
    Gattas GJ, Quade BJ, Nowak RA, Morton CC (1999) HMGIC expression in human adult and fetal tissues and in uterine leiomyomata. Genes Chromosomes Cancer 25:316–322PubMedCrossRefGoogle Scholar
  11. 11.
    Farnet CM, Bushman FD (1997) HIV-1 cDNA integration: requirement of HMG I(Y) protein for function of preintegration complexes in vitro. Cell 88:483–492PubMedCrossRefGoogle Scholar
  12. 12.
    Wang X, Liu X, Li AY, Chen L, Lai L, Lin HH, Hu S, Yao L, Peng J, Loera S, Xue L, Zhou B, Zhou L, Zheng S, Chu P, Zhang S, Ann DK, Yen Y (2011) Overexpression of HMGA2 promotes metastasis and impacts survival of colorectal cancers. Clin Cancer Res 17:2570–2580PubMedCrossRefGoogle Scholar
  13. 13.
    Meyer B, Loeschke S, Schultze A, Weigel T, Sandkamp M, Goldmann T, Vollmer E, Bullerdiek J (2007) HMGA2 overexpression in non-small cell lung cancer. Mol Carcinog 46:503–511PubMedCrossRefGoogle Scholar
  14. 14.
    Yang GL, Zhang LH, Bo JJ, Hou KL, Cai X, Chen YY, Li H, Liu DM, Huang YR (2011) Overexpression of HMGA2 in bladder cancer and its association with clinicopathologic features and prognosis HMGA2 as a prognostic marker of bladder cancer. Eur J Surg Oncol 37:265–271PubMedCrossRefGoogle Scholar
  15. 15.
    Hetland TE, Holth A, Kaern J, Florenes VA, Trope CG, Davidson B (2012) HMGA2 protein expression in ovarian serous carcinoma effusions, primary tumors, and solid metastases. Virchows Arch 460(5):505–513PubMedCrossRefGoogle Scholar
  16. 16.
    Fabjani G, Tong D, Wolf A, Roka S, Leodolter S, Hoecker P, Fischer MB, Jakesz R, Zeillinger R (2005) HMGA2 is associated with invasiveness but not a suitable marker for the detection of circulating tumor cells in breast cancer. Oncol Rep 14:737–741PubMedGoogle Scholar
  17. 17.
    Winkler S, Escobar HM, Meyer B, Simon D, Eberle N, Baumgartner W, Loeschke S, Nolte I, Bullerdiek J (2007) HMGA2 expression in a canine model of prostate cancer. Cancer Genet Cytogenet 177:98–102PubMedCrossRefGoogle Scholar
  18. 18.
    Wu J, Liu Z, Shao C, Gong Y, Hernando E, Lee P, Narita M, Muller W, Liu J, Wei JJ (2011) HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes. Cancer Res 71:349–359PubMedCrossRefGoogle Scholar
  19. 19.
    Thuault S, Tan EJ, Peinado H, Cano A, Heldin CH, Moustakas A (2008) HMGA2 and Smads co-regulate SNAIL1 expression during induction of epithelial-to-mesenchymal transition. J Biol Chem 283:33437–33446PubMedCrossRefGoogle Scholar
  20. 20.
    Hebert C, Norris K, Scheper MA, Nikitakis N, Sauk JJ (2007) High mobility group A2 is a target for miRNA-98 in head and neck squamous cell carcinoma. Mol Cancer 6:5PubMedCrossRefGoogle Scholar
  21. 21.
    Mayr C, Hemann MT, Bartel DP (2007) Disrupting the pairing between let-7 and Hmga2 enhances oncogenic transformation. Science 315:1576–1579PubMedCrossRefGoogle Scholar
  22. 22.
    Lee YS, Dutta A (2007) The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21:1025–1030PubMedCrossRefGoogle Scholar
  23. 23.
    Kalluri R, Weinberg RA (2009) The basics of epithelial-mesenchymal transition. J Clin Invest 119:1420–1428PubMedCrossRefGoogle Scholar
  24. 24.
    Eades G, Yao Y, Yang M, Zhang Y, Chumsri S, Zhou Q (2011) miR-200a regulates SIRT1 expression and epithelial to mesenchymal transition (EMT)-like transformation in mammary epithelial cells. J Biol Chem 286:25992–26002PubMedCrossRefGoogle Scholar
  25. 25.
    Malek A, Bakhidze E, Noske A, Sers C, Aigner A, Schafer R, Tchernitsa O (2008) HMGA2 gene is a promising target for ovarian cancer silencing therapy. Int J Cancer 123:348–356PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Chen Zhu
    • 1
  • Jie Li
    • 1
  • Gong Cheng
    • 1
  • Hai Zhou
    • 1
  • Liangjun Tao
    • 1
  • Hongzhou Cai
    • 1
  • Pu Li
    • 1
  • Qiang Cao
    • 1
  • Xiaobing Ju
    • 1
  • Xiaoxin Meng
    • 1
  • Meilin Wang
    • 2
  • Zhengdong Zhang
    • 2
  • Chao Qin
    • 1
  • Lixin Hua
    • 1
  • Changjun Yin
    • 1
    Email author
  • Pengfei Shao
    • 1
    Email author
  1. 1.State Key Laboratory of Reproductive Medicine, Department of UrologyThe First Affiliated Hospital of Nanjing Medical UniversityNanjingChina
  2. 2.Department of Molecular and Genetic ToxicologySchool of Public Health, Nanjing Medical UniversityNanjingChina

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