Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
권호 표지
DOI QR코드

DOI QR Code

Early Growth Response 1 Induces Epithelial-to-mesenchymal Transition via Snail

Egr-1-Snail 작용에 의한 epithelial-to-mesenchymal transition 유도

  • Jeon, Hyun Min (Department of Molecular Biology, College of Natural Sciences, Pusan National University) ;
  • Lee, Su Yeon (Department of Molecular Biology, College of Natural Sciences, Pusan National University) ;
  • Ju, Min Kyung (Department of Molecular Biology, College of Natural Sciences, Pusan National University) ;
  • Park, Hye Gyeong (Nanobiotechnology Center, Pusan National University) ;
  • Kang, Ho Sung (Department of Molecular Biology, College of Natural Sciences, Pusan National University)
  • 전현민 (부산대학 자연과학대학 분자생물학과) ;
  • 이수연 (부산대학 자연과학대학 분자생물학과) ;
  • 주민경 (부산대학 자연과학대학 분자생물학과) ;
  • 박혜경 (한국나노바이오테크놀러지센터) ;
  • 강호성 (부산대학 자연과학대학 분자생물학과)
  • Received : 2013.07.25
  • Accepted : 2013.08.08
  • Published : 2013.08.30
Download PDF
⟨ Previous Next ⟩

Abstract

The epithelial-to-mesenchymal transition (EMT) plays an essential role in embryogenesis and is involved in tumor metastasis and invasion; it significantly contributes to tumor progression and aggressiveness. The EMT is characterized by a loss of epithelial cell polarity as a result of the reduced expression of epithelial E-cadherin, a hallmark of the EMT, and the acquisition of mesenchymal-like cell morphology. Reactive oxygen species (ROS) such as $O_2{^-}$, $H_2O_2$, and $OH^-$ have been demonstrated to induce the EMT; although Snail is involved in ROS-induced EMT by transcriptionally repressing E-cadherin, its mechanism is not fully understood. In this study, we examined the effects of early growth response 1 (Egr-1) overexpression in noninvasive breast tumor cell line MCF-7 cells. Upon Egr-1 overexpression, MCF-7 cells lost epithelial cell polarity and became more spindle-shaped, indicating that Egr-1 may induce EMT. We found that Snail is implicated in Egr-1 induced EMT. We further demonstrate that the Egr-1-Snail axis is activated by ROS and plays a critical role(s) in ROS-induced EMT.

Epithelial-to-mesenchymal transition (EMT)는 embryogenesis에서 중요한 역할을 하며 tumor metastasis, invasion에도 관여함으로써 tumor progression 및 aggressiveness에 기여한다. EMT는 EMT hallmark인 epithelial E-cadherin의 발현 감소와 mesenchymal-like cell morphology를 획득함으로써 epithelial cell polarity를 잃어버리는 특징을 가지고 있다. $O_2{^-}$, $H_2O_2$, $OH^-$와 같은 활성산소가 EMT를 유도하는 것으로 알려져 있다. Snail이 E-cadherin의 발현을 억제함으로써 ROS에 의한 EMT에 관여하는 것으로 알려져 있으나, 그 기작은 완전히 밝혀져 있지 않다. 본 연구에서는, noninvasive breast tumor cell line인 MCF-7 세포에 Egr-1을 과발현시킨 후 그 영향을 조사하였다. Egr-1이 과발현되면, MCF-7 세포는 epithelial cell polarity를 잃고 spindle-shaped로 변화되므로, Egr-1이 EMT를 유도할 가능성이 대두되었다. 또한 Snail이 Egr-1에 의한 EMT에 관여함을 확인하였다. 나아가, 본 연구진은 Egr-1-Snail axis가 ROS에 의해 활성화 되고, ROS에 의한 EMT에서 중요한 역할을 함을 발견하였다.

Keywords

References

  1. Adamson, E. D. and Mercola, D. 2002. Egr1 transcription factor: multiple roles in prostate tumor cell growth and survival. Tumour Biol 23, 93-102. https://doi.org/10.1159/000059711
  2. Ahmed, M. M. 2004. Regulation of radiation-induced apoptosis by early growth response-1 gene in solid tumors. Curr Cancer Drug Targets 4, 43-52. https://doi.org/10.2174/1568009043481704
  3. Baron, V., Adamson, E. D., Calogero, A., Ragona, G. and Mercola, D. 2006. The transcription factor Egr1 is a direct regulator of multiple tumor suppressors including TGFbeta1, PTEN, p53, and fibronectin. Cancer Gene Ther 13, 115-124. https://doi.org/10.1038/sj.cgt.7700896
  4. Batlle, E., Sancho, E., Franci, C., Dominguez, D., Monfar, M., Baulida, J. and Garcia De Herreros, A. 2000. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2, 84-89. https://doi.org/10.1038/35000034
  5. Blanco, M. J., Moreno-Bueno, G., Sarrio, D., Locascio, A., Cano, A., Palacios, J. and Nieto, M. A. 2002. Correlation of Snail expression with histological grade and lymph node status in breast carcinomas. Oncogene 21, 3241-3246. https://doi.org/10.1038/sj.onc.1205416
  6. Cannito, S., Novo, E., di Bonzo, L. V., Busletta, C., Colombatto, S. and Parola, M. 2010. Epithelial-mesenchymal transition: from molecular mechanisms, redox regulation to implications in human health and disease. Antioxid Redox Signal 12, 1383-1430. https://doi.org/10.1089/ars.2009.2737
  7. Cat, B., Stuhlmann, D., Steinbrenner, H., Alili, L., Holtkotter, O., Sies, H. and Brenneisen, P. 2006. Enhancement of tumor invasion depends on transdifferentiation of skin fibroblasts mediated by reactive oxygen species. J Cell Sci 119, 2727-2738. https://doi.org/10.1242/jcs.03011
  8. Grotegut, S., von Schweinitz, D., Christofori, G. and Lehembre, F. 2006. Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. EMBO J 25, 3534-3545. https://doi.org/10.1038/sj.emboj.7601213
  9. Hussain, S. P., Hofseth, L. J. and Harris, C. C. 2003. Radical causes of cancer. Nat Rev Cancer 3, 276-285. https://doi.org/10.1038/nrc1046
  10. Jeon, H. M., Lee, S. Y., Ju, M. K., Kim, C. H., Park, H. G. and Kang, H. S. 2013. Early growth response 1 regulates glucose deprivation-induced necrosis. Oncol Rep 29, 669-675.
  11. Lee, S. Y., Jeon, H. M., Ju, M. K., Kim, C. H., Yoon, G., Han, S. I., Park, H. G. and Kang, H. S. 2012. Wnt/Snail signaling regulates cytochrome c oxidase and glucose metabolism. Cancer Res 72, 3607-3617. https://doi.org/10.1158/0008-5472.CAN-12-0006
  12. Lee, S. Y., Jeon, H. M., Kim, C. H., Ju, M. K., Bae, H. S., Park, H. G., Lim, S. C., Han, S. I. and Kang, H. S. 2011. Homeobox gene Dlx-2 is implicated in metabolic stress-induced necrosis. Mol Cancer 10, 113. https://doi.org/10.1186/1476-4598-10-113
  13. Liao, H., Hyman, M. C., Lawrence, D. A. and Pinsky, D. J. 2007. Molecular regulation of the PAI-1 gene by hypoxia: contributions of Egr-1, HIF-1alpha, and C/EBPalpha. FASEB J 21, 935-949. https://doi.org/10.1096/fj.06-6285com
  14. Lim, S. O., Gu, J. M., Kim, M. S., Kim, H. S., Park, Y. N., Park, C. K., Cho, J. W., Park, Y. M. and Jung, G. 2008. Epigenetic changes induced by reactive oxygen species in hepatocellular carcinoma: methylation of the E-cadherin promoter. Gastroenterology 135, 2128-2140, e2121-2128.
  15. Liu, Y. N., Lee, W. W., Wang, C. Y., Chao, T. H., Chen, Y. and Chen, J. H. 2005. Regulatory mechanisms controlling human E-cadherin gene expression. Oncogene 24, 8277-8290. https://doi.org/10.1038/sj.onc.1208991
  16. Lucerna, M., Pomyje, J., Mechtcheriakova, D., Kadl, A., Gruber, F., Bilban, M., Sobanov, Y., Schabbauer, G., Breuss, J., Wagner, O., Bischoff, M., Clauss, M., Binder, B. R. and Hofer, E. 2006. Sustained expression of early growth response protein-1 blocks angiogenesis and tumor growth. Cancer Res 66, 6708-6713. https://doi.org/10.1158/0008-5472.CAN-05-2732
  17. Mahalingam, D., Natoni, A., Keane, M., Samali, A. and Szegezdi, E. 2010. Early growth response-1 is a regulator of DR5-induced apoptosis in colon cancer cells. Br J Cancer 102, 754-764. https://doi.org/10.1038/sj.bjc.6605545
  18. Moody, S. E., Perez, D., Pan, T. C., Sarkisian, C. J., Portocarrero, C. P., Sterner, C. J., Notorfrancesco, K. L., Cardiff, R. D. and Chodosh, L. A. 2005. The transcriptional repressor Snail promotes mammary tumor recurrence. Cancer Cell 8, 197-209. https://doi.org/10.1016/j.ccr.2005.07.009
  19. Mori, K., Shibanuma, M. and Nose, K. 2004. Invasive potential induced under long-term oxidative stress in mammary epithelial cells. Cancer Res 64, 7464-7472. https://doi.org/10.1158/0008-5472.CAN-04-1725
  20. Nieto, M. A. 2002. The snail superfamily of zinc-finger transcription factors. Nat Rev Mol Cell Biol 3, 155-166. https://doi.org/10.1038/nrm757
  21. Nishi, H., Nishi, K. H. and Johnson, A. C. 2002. Early Growth Response-1 gene mediates up-regulation of epidermal growth factor receptor expression during hypoxia. Cancer Res 62, 827-834.
  22. Olmeda, D., Jorda, M., Peinado, H., Fabra, A. and Cano, A. 2007. Snail silencing effectively suppresses tumour growth and invasiveness. Oncogene 26, 1862-1874. https://doi.org/10.1038/sj.onc.1209997
  23. Pani, G., Galeotti, T. and Chiarugi, P. 2010. Metastasis: cancer cell's escape from oxidative stress. Cancer Metastasis Rev 29, 351-378. https://doi.org/10.1007/s10555-010-9225-4
  24. Pani, G., Giannoni, E., Galeotti, T. and Chiarugi, P. 2009. Redox-based escape mechanism from death: the cancer lesson. Antioxid Redox Signal 11, 2791-2806. https://doi.org/10.1089/ars.2009.2739
  25. Peinado, H., Olmeda, D. and Cano, A. 2007. Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7, 415-428. https://doi.org/10.1038/nrc2131
  26. Radisky, D. C., Levy, D. D., Littlepage, L. E., Liu, H., Nelson, C. M., Fata, J. E., Leake, D., Godden, E. L., Albertson, D. G., Nieto, M. A., Werb, Z. and Bissell, M. J. 2005. Rac1b and reactive oxygen species mediate MMP-3-induced EMT and genomic instability. Nature 436, 123-127. https://doi.org/10.1038/nature03688
  27. Rong, Y., Hu, F., Huang, R., Mackman, N., Horowitz, J. M., Jensen, R. L., Durden, D. L., Van Meir, E. G. and Brat, D. J. 2006. Early growth response gene-1 regulates hypoxia-induced expression of tissue factor in glioblastoma multiforme through hypoxia-inducible factor-1-independent mechanisms. Cancer Res 66, 7067-7074. https://doi.org/10.1158/0008-5472.CAN-06-0346
  28. Shi, D. Y., Xie, F. Z., Zhai, C., Stern, J. S., Liu, Y. and Liu, S. L. 2009. The role of cellular oxidative stress in regulating glycolysis energy metabolism in hepatoma cells. Mol Cancer 8, 32. https://doi.org/10.1186/1476-4598-8-32
  29. Sugimachi, K., Tanaka, S., Kameyama, T., Taguchi, K., Aishima, S., Shimada, M., Sugimachi, K. and Tsuneyoshi, M. 2003. Transcriptional repressor snail and progression of human hepatocellular carcinoma. Clin Cancer Res 9, 2657-2664.
  30. Thiel, G. and Cibelli, G. 2002. Regulation of life and death by the zinc finger transcription factor Egr-1. J Cell Physiol 193, 287-292. https://doi.org/10.1002/jcp.10178
  31. Thiery, J. P. and Sleeman, J. P. 2006. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol 7, 131-142. https://doi.org/10.1038/nrm1835
  32. Wagner, M., Schmelz, K., Dorken, B. and Tamm, I. 2008. Transcriptional regulation of human survivin by early growth response (Egr)-1 transcription factor. Int J Cancer 122, 1278-1287.
  33. Xie, B., Wang, C., Zheng, Z., Song, B., Ma, C., Thiel, G. and Li, M. 2011. Egr-1 transactivates Bim gene expression to promote neuronal apoptosis. J Neurosci 31, 5032-5044. https://doi.org/10.1523/JNEUROSCI.5504-10.2011
  34. Yamaguchi, H., Chen, C. T., Chou, C. K., Pal, A., Bornmann, W., Hortobagyi, G. N. and Hung, M. C. 2010. Adenovirus 5 E1A enhances histone deacetylase inhibitors-induced apoptosis through Egr-1-mediated Bim upregulation. Oncogene 29, 5619-5629. https://doi.org/10.1038/onc.2010.295
  35. Yook, J. I., Li, X. Y., Ota, I., Hu, C., Kim, H. S., Kim, N. H., Cha, S. Y., Ryu, J. K., Choi, Y. J., Kim, J., Fearon, E. R. and Weiss, S. J. 2006. A Wnt-Axin2-GSK3beta cascade regulates Snail1 activity in breast cancer cells. Nat Cell Biol 8, 1398-1406. https://doi.org/10.1038/ncb1508
  36. Zagurovskaya, M., Shareef, M. M., Das, A., Reeves, A., Gupta, S., Sudol, M., Bedford, M. T., Prichard, J., Mohiuddin, M. and Ahmed, M. M. 2009. EGR-1 forms a complex with YAP-1 and upregulates Bax expression in irradiated prostate carcinoma cells. Oncogene 28, 1121-1131. https://doi.org/10.1038/onc.2008.461
  37. Zavadil, J. and Bottinger, E. P. 2005. TGF-beta and epithelial-to-mesenchymal transitions. Oncogene 24, 5764-5774. https://doi.org/10.1038/sj.onc.1208927
  38. Zhang, P., Tchou-Wong, K. M. and Costa, M. 2007. Egr-1 mediates hypoxia-inducible transcription of the NDRG1 gene through an overlapping Egr-1/Sp1 binding site in the promoter. Cancer Res 67, 9125-9133. https://doi.org/10.1158/0008-5472.CAN-07-1525

Cited by

  1. NF-kappaΒ-inducing kinase regulates stem cell phenotype in breast cancer vol.6, pp.1, 2016, https://doi.org/10.1038/srep37340