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HOXB5 Directly Regulates the Expression of IL-6 in MCF7 Breast Cancer Cells

  • Kim, Jie Min (Department of Anatomy, Embryology Laboratory, and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine) ;
  • Lee, Ji-Yeon (Department of Anatomy, Embryology Laboratory, and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine) ;
  • Kim, Myoung Hee (Department of Anatomy, Embryology Laboratory, and Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine)
  • Received : 2017.07.02
  • Accepted : 2017.08.24
  • Published : 2017.09.30

Abstract

HOX genes are transcription factors that play important roles in body patterning and cell fate specification during normal development. In previous study, we found aberrant overexpression of HOXB5 in breast cancer tissues and cell lines, and demonstrated that HOXB5 is important in regulation of cell proliferation, tamoxifen resistance, and invasiveness through the epithelial-mesenchymal transition (EMT). Although the relationship between HOXB5 and phenotypic changes in MCF7 breast cancer cells has been studied, the molecular function of HOXB5 as a transcription factor remains unclear. IL-6 has been reported to be involved in not only inflammation but also cancer progression, which is characterized by the increase of growth speed and invasiveness of tumor cells. In this study, we selected Interleukin-6 (IL-6) as HOXB5 putative downstream target gene and discovered that HOXB5 transcriptionally up-regulated the expression of IL-6 in HOXB5 overexpressing MCF7 cells. The upstream region (~1.2 kb) of IL-6 promoter turned out to contain several putative HOX consensus binding sites. Chromatin immunoprecipitation assay confirmed that HOXB5 directly binds to the promoter region of IL-6 and positively regulated the expression of IL-6. These data all together, indicate that HOXB5 promotes IL-6 transcription by actively binding to the putative binding sites located in the upstream region of IL-6, which enable to increase its promoter activity in MCF7 breast cancer cells.

Keywords

References

  1. Abe M, Hamada J, Takahashi O, Takahashi Y, Tada M, Miyamoto M, Morikawa T, Kondo S, Moriuchi T. Disordered expression of HOX genes in human non-small cell lung cancer. Oncology Reports. 2006. 15: 797-802.
  2. Allison KH. Molecular pathology of breast cancer: what a pathologist needs to know. Journal Of Clinical Pathology. 2012. 138: 770-780. https://doi.org/10.1309/AJCPIV9IQ1MRQMOO
  3. Cillo C, Barba P, Freschi G, Bucciarelli G, Magli MC, Boncinelli E. HOX gene expression in normal and neoplastic human kidney. International Journal of Cancer. 1992. 51: 892-897. https://doi.org/10.1002/ijc.2910510610
  4. Coussens LM, Zitvogel L, Palucka AK. Neutralizing tumorpromoting chronic inflammation: a magic bullet? Science. 2013. 339: 286-291. https://doi.org/10.1126/science.1232227
  5. Fessner A, Esser JS, Bluhm F, Grundmann S, Zhou Q, Patterson C, Bode C, Moser M. The transcription factor HoxB5 stimulates vascular remodelling in a cytokine-dependent manner. Cardiovascular Research. 2014. 101: 247-255. https://doi.org/10.1093/cvr/cvt244
  6. Gehring WJ, Hiromi Y. Homeotic genes and the homeobox. Annual Review of Genetics. 1986. 20: 147-173. https://doi.org/10.1146/annurev.ge.20.120186.001051
  7. Hong CS, Jeong O, Piao Z, Guo C, Jung MR, Choi C, Park YK. HOXB5 induces invasion and migration through direct transcriptional up-regulation of beta-catenin in human gastric carcinoma. Biochemical Journal. 2015. 472: 393-403. https://doi.org/10.1042/BJ20150213
  8. Hur H, Lee JY, Yun HJ, Park BW, Kim MH. Analysis of HOX gene expression patterns in human breast cancer. Molecular Biotechnology. 2014. 56: 64-71. https://doi.org/10.1007/s12033-013-9682-4
  9. Kam MK, Cheung MC, Zhu JJ, Cheng WW, Sat EW, Tam PK, Lui VC. Perturbation of Hoxb5 signaling in vagal and trunk neural crest cells causes apoptosis and neurocristopathies in mice. Cell Death & Differentiation. 2014. 21: 278-289. https://doi.org/10.1038/cdd.2013.142
  10. Lee JY, Hur H, Yun HJ, Kim Y, Yang S, Kim SI, Kim MH. HOXB5 promotes the proliferation and invasion of breast cancer cells. International Journal of Biological Sciences. 2015. 11: 701-711. https://doi.org/10.7150/ijbs.11431
  11. Li H, Huang CJ, Choo KB. Expression of homeobox genes in cervical cancer. Gynecologic Oncology. 2002. 84: 216-221. https://doi.org/10.1006/gyno.2001.6498
  12. Lin S, Gan Z, Han K, Yao Y, Min D. Interleukin-6 as a prognostic marker for breast cancer: a meta-analysis. Tumori Journal. 2015. 101: 535-541. https://doi.org/10.5301/tj.5000357
  13. Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008. 454: 436-444. https://doi.org/10.1038/nature07205
  14. Shah N, Jin K, Cruz LA, Park S, Sadik H, Cho S, Goswami CP, Nakshatri H, Gupta R, Chang HY, Zhang Z, Cimino-Mathews A, Cope L, Umbricht C, Sukumar S. HOXB13 mediates tamoxifen resistance and invasiveness in human breast cancer by suppressing ERalpha and inducing IL-6 expression. Cancer Research. 2013. 73: 5449-5458. https://doi.org/10.1158/0008-5472.CAN-13-1178
  15. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA: A Cancer Journal for Clinicians. 2016. 66: 7-30. https://doi.org/10.3322/caac.21332
  16. Spitz F, Furlong EE. Transcription factors: from enhancer binding to developmental control. Nature Reviews Genetics. 2012. 13:613-626. https://doi.org/10.1038/nrg3207
  17. Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N, Oberyszyn TM, Hall BM. Interleukin-6 induces an epithelialmesenchymal transition phenotype in human breast cancer cells. Oncogene. 2009. 28: 2940-2947. https://doi.org/10.1038/onc.2009.180
  18. Sun KY, Peng T, Chen Z, Huang J, Zhou XH. MicroRNA-1275 suppresses cell growth, and retards G1/S transition in human nasopharyngeal carcinoma by down-regulation of HOXB5. Journal of Cell Communication and Signaling. 2016. 10: 305-314. https://doi.org/10.1007/s12079-016-0351-9
  19. Wang KC, Helms JA, Chang HY. Regeneration, repair and remembering identity: the three Rs of Hox gene expression. Trends in Cell Biology. 2009. 19: 268-275. https://doi.org/10.1016/j.tcb.2009.03.007
  20. Zhang B, Li N, Zhang H. Knockdown of Homeobox B5 (HOXB5) inhibits cell proliferation, migration, and invasion in non-small cell lung cancer cells through inactivation of the Wnt/betacatenin pathway. Oncology Research. 2017. 7: 81527-81540.
  21. Zhu J, Garcia-Barcelo MM, Tam PK, Lui VC. HOXB5 cooperates with NKX2-1 in the transcription of human RET. PLoS One. 2011. 6: e20815. https://doi.org/10.1371/journal.pone.0020815