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HMGA2 Elicits EMT by Activating the Wnt/β-catenin Pathway in Gastric Cancer

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Abstract

Background

The high mobility group protein A2 (HMGA2) is an architectural transcription factor that plays an important role in the development and progression of many malignant neoplasms. High expression of HMGA2 in gastric cancer correlates with invasiveness of cancer and is an independent prognostic factor. The reason for this might be HMGA2 promoting epithelial–mesenchymal transitions (EMT), which is the key process of metastasis for some underlying mechanisms.

Aims

This study was designed to test whether HMGA2 participates in the EMT and to further understand the underlying mechanisms of EMT promoted by HMGA2.

Methods

We examined the cell biology and molecular biology changes after overexpression and knockdown HMGA2 of gastric cancer cells in vitro and vivo. To further understand the underlying mechanisms of EMT promoted by HMGA2, based on our previous study, we examined the changes of target genes of HMGA2 after overexpression and knockdown HMGA2 of gastric cancer cells.

Results

The results indicated that overexpressing HMGA2 enabled enhancing the oncogenic properties of gastric epithelial origin cell in vitro and in vivo. Furthermore, our study showed that HMGA2 was able to elicit EMT and regulate several genes which are closely related to the Wnt/β-catenin pathway by directly binding to their promoter thereby activating the Wnt/β-catenin pathway.

Conclusions

The Wnt/β-catenin pathway activated by HMGA2 might be the underlying mechanism of EMT in gastric cancer cells.

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References

  1. Parkin DM, Bray F, Ferlay J, et al. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.

    Article  PubMed  Google Scholar 

  2. Wu Y, Zhou BP. New insights of epithelial–mesenchymal transition in cancer metastasis. Acta Biochim Biophys Sin (Shanghai). 2008;40:643–650.

    Article  CAS  Google Scholar 

  3. Fuxe J, Vincent T, Garcia de Herreros A. Transcriptional crosstalk between TGF-beta and stem cell pathways in tumor cell invasion: role of EMT promoting Smad complexes. Cell Cycle. 2010;9:2363–2374.

    Article  PubMed  CAS  Google Scholar 

  4. Bates RC, Mercurio AM. The epithelial–mesenchymal transition (EMT) and colorectal cancer progression. Cancer Biol Ther. 2005;4:365–370.

    Article  PubMed  CAS  Google Scholar 

  5. Thiery JP, Acloque H, Huang RY, et al. Epithelial–mesenchymal transitions in development and disease. Cell. 2009;139:871–890.

    Article  PubMed  CAS  Google Scholar 

  6. Eramo A, Haas TL, De Maria R. Lung cancer stem cells: tools and targets to fight lung cancer. Oncogene. 2010;29:4625–4635.

    Article  PubMed  CAS  Google Scholar 

  7. Kratz JR, Yagui-Beltran A, Jablons DM. Cancer stem cells in lung tumorigenesis. Ann Thorac Surg. 2010;89:S2090–S2095.

    Article  PubMed  Google Scholar 

  8. Dirks PB. Cancer: stem cells and brain tumours. Nature. 2006;444:687–688.

    Article  PubMed  CAS  Google Scholar 

  9. Biddle A, Liang X, Gammon L, et al. Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res. 2011;71:5317–5326.

    Article  PubMed  CAS  Google Scholar 

  10. Chen C, Wei Y, Hummel M, et al. Evidence for epithelial–mesenchymal transition in cancer stem cells of head and neck squamous cell carcinoma. PLoS One. 2011;6:e16466.

    Article  PubMed  CAS  Google Scholar 

  11. Mani SA, Guo W, Liao MJ, et al. The epithelial–mesenchymal transition generates cells with properties of stem cells. Cell. 2008;133:704–715.

    Article  PubMed  CAS  Google Scholar 

  12. Hock R, Furusawa T, Ueda T, et al. HMG chromosomal proteins in development and disease. Trends Cell Biol. 2007;17:72–79.

    Article  PubMed  CAS  Google Scholar 

  13. Meyer B, Loeschke S, Schultze A, et al. HMGA2 overexpression in non-small cell lung cancer. Mol Carcinog. 2007;46:503–511.

    Article  PubMed  CAS  Google Scholar 

  14. Langelotz C, Schmid P, Jakob C, et al. Expression of high-mobility-group-protein HMGI-C mRNA in the peripheral blood is an independent poor prognostic indicator for survival in metastatic breast cancer. Br J Cancer. 2003;88:1406–1410.

    Article  PubMed  CAS  Google Scholar 

  15. Belge G, Meyer A, Klemke M, et al. Upregulation of HMGA2 in thyroid carcinomas: a novel molecular marker to distinguish between benign and malignant follicular neoplasias. Genes Chromosom Cancer. 2008;47:56–63.

    Article  PubMed  CAS  Google Scholar 

  16. Motoyama K, Inoue H, Nakamura Y, et al. Clinical significance of high mobility group A2 in human gastric cancer and its relationship to let-7 microRNA family. Clin Cancer Res. 2008;14:2334–2340.

    Article  PubMed  CAS  Google Scholar 

  17. Miyazawa J, Mitoro A, Kawashiri S, et al. Expression of mesenchyme-specific gene HMGA2 in squamous cell carcinomas of the oral cavity. Cancer Res. 2004;64:2024–2029.

    Article  PubMed  CAS  Google Scholar 

  18. Thuault S, Valcourt U, Petersen M, et al. Transforming growth factor-beta employs HMGA2 to elicit epithelial–mesenchymal transition. J Cell Biol. 2006;174:175–183.

    Article  PubMed  CAS  Google Scholar 

  19. Watanabe S, Ueda Y, Akaboshi S, et al. HMGA2 maintains oncogenic RAS-induced epithelial–mesenchymal transition in human pancreatic cancer cells. Am J Pathol. 2009;174:854–868.

    Article  PubMed  CAS  Google Scholar 

  20. Wu J, Liu Z, Shao C, et al. HMGA2 overexpression-induced ovarian surface epithelial transformation is mediated through regulation of EMT genes. Cancer Res. 2011;71:349–359.

    Article  PubMed  CAS  Google Scholar 

  21. Nishino J, Kim I, Chada K, et al. Hmga2 promotes neural stem cell self-renewal in young but not old mice by reducing p16Ink4a and p19Arf expression. Cell. 2008;135:227–239.

    Article  PubMed  CAS  Google Scholar 

  22. Yu F, Yao H, Zhu P, et al. let-7 Regulates self renewal and tumorigenicity of breast cancer cells. Cell. 2007;131:1109–1123.

    Article  PubMed  CAS  Google Scholar 

  23. Zha L, Wang Z, Tang W, et al. Genome-wide analysis of HMGA2 transcription factor binding sites by ChIP on chip in gastric carcinoma cells. Mol Cell Biochem. 2012;364:243–251.

    Article  PubMed  CAS  Google Scholar 

  24. Thiery JP. Epithelial–mesenchymal transitions in tumour progression. Nat Rev Cancer. 2002;2:442–454.

    Article  PubMed  CAS  Google Scholar 

  25. Khan NP, Pandith AA, Hussain MU, et al. Novelty of Axin 2 and lack of Axin 1 gene mutation in colorectal cancer: a study in Kashmiri population. Mol Cell Biochem. 2011;355:149–155.

    Article  PubMed  CAS  Google Scholar 

  26. Levayer R, Lecuit T. Breaking down EMT. Nat Cell Biol. 2008;10:757–759.

    Article  PubMed  CAS  Google Scholar 

  27. Schoenmakers EF, Wanschura S, Mols R, et al. Recurrent rearrangements in the high mobility group protein gene, HMGI-C, in benign mesenchymal tumours. Nat Genet. 1995;10:436–444.

    Article  PubMed  CAS  Google Scholar 

  28. Pozharskaya V, Torres-Gonzalez E, Rojas M, et al. Twist: a regulator of epithelial-mesenchymal transition in lung fibrosis. PLoS One. 2009;4:e7559.

    Article  PubMed  Google Scholar 

  29. Yu L, Li HZ, Lu SM, et al. Down-regulation of TWIST decreases migration and invasion of laryngeal carcinoma Hep-2 cells by regulating the E-cadherin, N-cadherin expression. J Cancer Res Clin Oncol. 2011;137:1487–1493.

    Article  PubMed  CAS  Google Scholar 

  30. Pfannkuche K, Summer H, Li O, et al. The high mobility group protein HMGA2: a co-regulator of chromatin structure and pluripotency in stem cells? Stem Cell Rev. 2009;5:224–230.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The project was supported by the National Natural Science Foundation of China (No. 81272753).

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Gastrointestinal Surgery, First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Lang Zha, Neng Zhang, Miao He, Yi Guo & Ziwei Wang

  2. Department of Obstetrics and Gynecology, First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China

    Jing Zhang

  3. Key Laboratory of General Surgery in Chongqing, Chongqing, 400016, People’s Republic of China

    Weixue Tang

Authors
  1. Lang Zha
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  2. Jing Zhang
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  3. Weixue Tang
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  4. Neng Zhang
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  5. Miao He
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  6. Yi Guo
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  7. Ziwei Wang
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Corresponding author

Correspondence to Ziwei Wang.

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Zha, L., Zhang, J., Tang, W. et al. HMGA2 Elicits EMT by Activating the Wnt/β-catenin Pathway in Gastric Cancer. Dig Dis Sci 58, 724–733 (2013). https://doi.org/10.1007/s10620-012-2399-6

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  • DOI: https://doi.org/10.1007/s10620-012-2399-6

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