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Journal of Biosciences

, Volume 41, Issue 2, pp 229–236 | Cite as

Silencing of HMGA2 promotes apoptosis and inhibits migration and invasion of prostate cancer cells

  • Zhan Shi
  • Ding Wu
  • Run Tang
  • Xiang Li
  • Renfu Chen
  • Song Xue
  • Chengjing Zhang
  • Xiaoqing SunEmail author
Article

Abstract

The high mobility group protein A2 (HMGA2) has been demonstrated as an architectural transcription factor that is associated with pathogenesis of many malignant cancers; however, its role in prostate cancer cells remains largely unknown. To explore whether HMGA2 participates in the development and progression of prostate cancer, small interfering RNA (siRNA) targeted on human HMGA2 was transfected to suppress the HMGA2 expression in prostate cancer PC3 and DU145 cells, and then the cellular biology changes after decreased the expression of HMGA2 was examined. Our results showed that knockdown of HMGA2 markedly inhibited cell proliferation; this reduced cell proliferation was due to the promotion of cell apoptosis as the Bcl-xl was decreased, whereas Bax was up-regulated. In addition, we found that HMGA2 knockdown resulted in reduction of cell migration and invasion, as well as repressed the expression of matrix metalloproteinases (MMPs) and affected the occurrence of epithelial-mesenchymal transition (EMT) in both cell types. We further found that decreased HMGA2 expression inhibited the transforming growth factor-β (TGF-β)/Smad signalling pathway in cancer cells. In conclusion, our data indicated that HMGA2 was associated with apoptosis, migration and invasion of prostate cancer, which might be a promising therapeutic target for prostate cancer.

Keywords

Apoptosis epithelial-mesenchymal transition HMGA2 metastasis prostate cancer 

References

  1. Siegel RL, Miller KD and Jemal A 2015 Cancer statistics, 2015. CA Cancer J. Clin. 65 5–29CrossRefPubMedGoogle Scholar
  2. DiBlasio CJ, Malcolm JB, Hammett J, Wan JY, Aleman MA, Patterson AL, Wake RW and Derweesh IH 2009 Survival outcomes in men receiving androgen-deprivation therapy as primary or salvage treatment for localized or advanced prostate cancer: 20-year single-centre experience. BJU Int. 104 1208–1214CrossRefPubMedGoogle Scholar
  3. Ramsay AK, McCracken SR, Soofi M, Fleming J, Yu AX, Ahmad I, Morland R, Machesky L, et al. 2011 ERK5 signalling in prostate cancer promotes an invasive phenotype. Br. J. Cancer 104 664–672CrossRefPubMedPubMedCentralGoogle Scholar
  4. Maruyama Y, Miyazaki T, Ikeda K, Okumura T, Sato W, Horie-Inoue K, Okamoto K, Takeda S, et al. 2014 Short hairpin RNA library-based functional screening identified ribosomal protein L31 that modulates prostate cancer cell growth via p53 pathway. PLoS One 9 e108743CrossRefPubMedPubMedCentralGoogle Scholar
  5. Zha L, Wang Z, Tang W, Zhang N, Liao G and Huang Z 2012 Genome-wide analysis of HMGA2 transcription factor binding sites by ChIP on chip in gastric carcinoma cells. Mol. Cell. Biochem. 364 243–251CrossRefPubMedGoogle Scholar
  6. Liu Z, Wu K, Yang Z and Wu A 2015 High-mobility group A2 overexpression is an unfavorable prognostic biomarker for nasopharyngeal carcinoma patients. Mol. Cell. Biochem. 409 155–162CrossRefPubMedGoogle Scholar
  7. Luo Y, Li W and Liao H 2013 HMGA2 induces epithelial-to-mesenchymal transition in human hepatocellular carcinoma cells. Oncol. Lett. 5 1353–1356PubMedPubMedCentralGoogle Scholar
  8. Venkatesan N, Krishnakumar S, Deepa PR, Deepa M, Khetan V and Reddy MA 2012 Molecular deregulation induced by silencing of the high mobility group protein A2 gene in retinoblastoma cells. Mol. Vis. 18 2420–2437PubMedPubMedCentralGoogle Scholar
  9. Morishita A, Zaidi MR, Mitoro A, Sankarasharma D, Szabolcs M, Okada Y, D'Armiento J and Chada K 2013 HMGA2 is a driver of tumor metastasis. Cancer Res. 73 4289–4299CrossRefPubMedPubMedCentralGoogle Scholar
  10. Zhu C, Li J, Cheng G, Zhou H, Tao L, Cai H, Li P, Cao Q, et al. 2013 miR-154 inhibits EMT by targeting HMGA2 in prostate cancer cells. Mol. Cell. Biochem. 379 69–75CrossRefPubMedGoogle Scholar
  11. Zou Q, Xiong L, Yang Z, Lv F, Yang L and Miao X 2012 Expression levels of HMGA2 and CD9 and its clinicopathological significances in the benign and malignant lesions of the gallbladder. World J. Surg. Oncol. 10 92CrossRefPubMedPubMedCentralGoogle Scholar
  12. Li Y, Zhao Z, Xu C, Zhou Z, Zhu Z and You T 2014a HMGA2 induces transcription factor Slug expression to promote epithelial-to-mesenchymal transition and contributes to colon cancer progression. Cancer Lett. 355 130–140CrossRefPubMedGoogle Scholar
  13. Tiwari N, Gheldof A, Tatari M and Christofori G 2012 EMT as the ultimate survival mechanism of cancer cells. Semin. Cancer Biol. 22 194–207CrossRefPubMedGoogle Scholar
  14. Yilmaz M and Christofori G 2009 EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 28 15–33CrossRefPubMedGoogle Scholar
  15. Thiery JP, Acloque H, Huang RY and Nieto MA 2009 Epithelial-mesenchymal transitions in development and disease. Cell 139 871–890CrossRefPubMedGoogle Scholar
  16. McConkey DJ, Choi W, Marquis L, Martin F, Williams MB, Shah J, Svatek R, Das A, et al. 2009 Role of epithelial-to-mesenchymal transition (EMT) in drug sensitivity and metastasis in bladder cancer. Cancer Metastasis Rev. 28 335–344CrossRefPubMedGoogle Scholar
  17. Zhang HJ, Wang HY, Zhang HT, Su JM, Zhu J, Wang HB, Zhou WY, Zhang H, et al. 2011 Transforming growth factor-beta1 promotes lung adenocarcinoma invasion and metastasis by epithelial-to-mesenchymal transition. Mol. Cell. Biochem. 355 309–314CrossRefPubMedGoogle Scholar
  18. Kayastha F, Johar K, Gajjar D, Arora A, Madhu H, Ganatra D and Vasavada A 2015 Andrographolide suppresses epithelial mesenchymal transition by inhibition of MAPK signalling pathway in lens epithelial cells. J. Biosci. 40 313–324CrossRefPubMedGoogle Scholar
  19. Lu YJ, Geng ZJ, Sun XY, Li YH, Fu XB, Zhao XY and Wei B 2015 Isoprenaline induces epithelial-mesenchymal transition in gastric cancer cells. Mol. Cell. Biochem. 408 1–13CrossRefPubMedGoogle Scholar
  20. Li X, Li P, Chang Y, Xu Q, Wu Z, Ma Q and Wang Z 2014b The SDF-1/CXCR4 axis induces epithelial-mesenchymal transition in hepatocellular carcinoma. Mol. Cell. Biochem. 392 77–84CrossRefPubMedGoogle Scholar
  21. Kessenbrock K, Plaks V and Werb Z 2010 Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141 52–67CrossRefPubMedPubMedCentralGoogle Scholar
  22. Slattery ML, John E, Torres-Mejia G, Stern M, Lundgreen A, Hines L, Giuliano A, Baumgartner K, et al. 2013 Matrix metalloproteinase genes are associated with breast cancer risk and survival: The Breast Cancer Health Disparities Study. PLoS One 8 e63165CrossRefPubMedPubMedCentralGoogle Scholar
  23. De Craene B and Berx G 2013 Regulatory networks defining EMT during cancer initiation and progression. Nat. Rev. Cancer. 13 97–110CrossRefPubMedGoogle Scholar
  24. Yang H, Zhan L, Yang T, Wang L, Li C, Zhao J, Lei Z, Li X, et al. 2015 Ski prevents TGF-beta-induced EMT and cell invasion by repressing SMAD-dependent signaling in non-small cell lung cancer. Oncol. Rep. 34 87–94PubMedGoogle Scholar
  25. Xia YY, Yin L, Tian H, Guo WJ, Jiang N, Jiang XS, Wu J, Chen M, et al. 2015 HMGA2 is associated with epithelial-mesenchymal transition and can predict poor prognosis in nasopharyngeal carcinoma. Onco Targets Ther. 8 169–176CrossRefPubMedPubMedCentralGoogle Scholar
  26. Dalvi MP, Umrani MR, Joglekar MV and Hardikar AA 2009 Human pancreatic islet progenitor cells demonstrate phenotypic plasticity in vitro. J. Biosci. 34 523–528CrossRefPubMedGoogle Scholar
  27. Lander R, Nordin K and LaBonne C 2011 The F-box protein Ppa is a common regulator of core EMT factors Twist, Snail, Slug, and Sip1. J. Cell Biol. 194 17–25CrossRefPubMedPubMedCentralGoogle Scholar
  28. Diaz VM, Vinas-Castells R and Garcia de Herreros A 2014 Regulation of the protein stability of EMT transcription factors. Cell Adhes. Migr. 8 418–428CrossRefGoogle Scholar

Copyright information

© Indian Academy of Sciences 2016

Authors and Affiliations

  • Zhan Shi
    • 1
  • Ding Wu
    • 1
  • Run Tang
    • 1
  • Xiang Li
    • 1
  • Renfu Chen
    • 1
  • Song Xue
    • 1
  • Chengjing Zhang
    • 1
  • Xiaoqing Sun
    • 1
    Email author
  1. 1.Department of UrologyThe Affiliated Hospital of Xuzhou Medical CollegeXuzhouChina

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