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Fra-1 Regulates the Expression of HMGA1, Which is Associated with a Poor Prognosis in Human Esophageal Squamous Cell Carcinoma

  • Translational Research and Biomarkers
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

The expression of Fos-related antigen 1 (Fra-1) affects tumor progression, migration, and invasion. In this study, we identified the genes regulated by Fra-1 in esophageal squamous cell carcinoma (ESCC).

Methods

We constructed Fra-1 knockdown models via the transfection of small interfering RNA (siRNA) into ESCC cell lines (TE10, TE11). The expression levels of the genes in the knockdown models were analyzed using a microarray and a Biobase Upstream Analysis, while the expression levels of the candidate genes in the primary tumors of surgical specimens obtained from ESCC patients were determined using real-time polymerase chain reaction (PCR) and immunohistochemical staining. The clinicopathological features were then analyzed.

Results

The Biobase Upstream Analysis showed the high-mobility-group protein-1 (HMGA1) to be a significant gene regulated by Fra-1. Actual binding of Fra-1 to the promotor region of HMGA1 was revealed in subsequent chromatin immunoprecipitation PCR experiments. Patients with a positive HMGA1 expression had a poor prognosis, and a multivariate analysis demonstrated a positive HMGA1 expression to be a significant independent prognostic factor.

Conclusion

HMGA1 is regulated by Fra-1 in ESCC, and the HMGA1 expression is significantly associated with a poor prognosis in ESCC patients. Downregulation of the HMGA1 expression may become a practical treatment strategy against ESCC in the future.

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References

  1. Courrech Staal EF, van Coevorden F, Cats A, et al. Outcome of low-volume surgery for esophageal cancer in a high-volume referral center. Ann Surg Oncol. 2009;16:3219–26.

    Article  PubMed  Google Scholar 

  2. Law SY, Fok M, Chen SW. Wong J. A comparison of outcome after resection for sequamous cell carcinomas and adenocarcinomas of the esophagus and cardia. Surg Gynecol Obstet. 1992;175:107–12.

    CAS  PubMed  Google Scholar 

  3. Curran T, Franza BR Jr. Fos and Jun: the AP-1 connection. Cell. 1998;55:395–7.

    Article  Google Scholar 

  4. Angel P, Karin M. Specific members of the Jun protein family regulate collagenase expression in response to various extracellular stimuli. Matrix Suppl. 1992;1:156–4.

    CAS  PubMed  Google Scholar 

  5. Mechta F, Lallemand D, Pfarr CM, et al. Transformation by ras modifies AP1 composition and activity. Oncogene. 1997;14:837–7.

    Article  CAS  PubMed  Google Scholar 

  6. Kakumoto K, Sasai K, Sukezawa T, et al. FRA1 is a determinant for the difference in RAS-induced transformation between human and rat fibroblasts. Proc Natl Acad Sci USA. 2006;103:5490–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Usui A, Hoshino I, Akutsu Y, et al. The molecular role of Fra-1 and its prognostic significance in human esophageal squamous cell carcinoma. Cancer. 2012;118:3387–6.

    Article  CAS  PubMed  Google Scholar 

  8. Akanuma N, Hoshino I, Akutsu Y, et al. MicroRNA-133a regulates the mRNAs of two invadopodia-related proteins, FSCN1 and MMP14, in esophageal cancer. Br J Cancer. 2014;110:189–8.

    Article  CAS  PubMed  Google Scholar 

  9. Nishihira T, Hashimoto Y, Katayama M, et al. Molecular and cellular features of esophageal cancer cells. J Cancer Res Clin Oncol. 1993;119:441–9.

    Article  CAS  PubMed  Google Scholar 

  10. Kel AE, Gobling E, Reuter I, et al. MATCH: a tool for searching transcription factor binding sites in DNA sequences. Nucleic Acids Res. 2003;31:3576–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Wingender E, Chen X, Hehl R, et al. TRANSFAC: an intergrade system for gene expression regulation. Nucleic Acids Res. 2000;28:316–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ameyar-Zazoua M, Wisniewska MB, Bakiri L, et al. AP-1 dimers regulate transcription of the p14/p19ARF tumor suppressor gene. Oncogene. 2005;24:2298–6.

    Article  CAS  PubMed  Google Scholar 

  13. Belfuise K, Kersual N, Galtier F, et al. FRA-1 expression level regulates proliferation and invasiveness of breast cancer cells. Oncogene. 2005;24:1434–4.

    Article  Google Scholar 

  14. Burch PM, Yuan Z, Loonen A, et al. An extracellular sgnal-regulated kinase1- and 2-dependent program of chromatin trafficking of c-Fos and Fra-1 is required for cyclin D1 expression during cell cycle reentry. Mol Cell Biol. 2004;24:4696–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang Q, Adiseshaiah P, Reddv SP. Matrix metalloproteinase/epidermal growth factor receptor/mitogen-activated protein kinase signaling regulate fra-1 induction by cigarette smoke in lung epithelial cells. Am J Respir Cell Mol Biol. 2005;32:72–1.

    Article  PubMed  Google Scholar 

  16. Hommura F, Katabami M, Leaner VD, et al. HMG-I/Y is a c-Jun/activator protein-1 target gene and is necessary for c-Jun-induced anchorage-independent growth in Rat1a cells. Mol Cancer Res. 2004;2:305–4.

    CAS  PubMed  Google Scholar 

  17. Wood LJ, Mukherjee M, Dolde CE, et al. HMG-I/Y: a new c-Myc target gene and potential human oncogene. Mol Cell Biol. 2000;20:5490–2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Dhar A, Hu J, Reeves R, et al. Dominant negative c-Jun (TAM67) target genes: HMGA1 is required for tumor promoter-induced transformation. Oncogene. 2004;23:4466–6.

    Article  CAS  PubMed  Google Scholar 

  19. Giannini G, Cerignoli F, Mellone M, et al. High mobility group A1 is a molecular target for MYCN in human neuroblastoma. Cancer Res. 2005;65:8308–6.

    Article  CAS  PubMed  Google Scholar 

  20. Giannini G, Cerignoli F, Mellone M, et al. Molecular mechanism of HMGA1 deregulation in human neuroblastoma. Cancer Lett. 2005;228:97–104.

    Article  CAS  PubMed  Google Scholar 

  21. Pedulla ML, Treff NR, Resar LM, et al. Sequence and analysis of the murine Hmgiy (Hmga1) gene locus. Gene. 2001;271:51–8.

    Article  CAS  PubMed  Google Scholar 

  22. Sgarra R, Rustighi A, Tessari MA, et al. Nuclear phosphoproteins HMGA and their relationship with chromatin structure and cancer. FEBS Lett. 2004;574:1–8.

    Article  CAS  PubMed  Google Scholar 

  23. Johnson KR, Cook SA, Davisson MT. Chromosomal localization of the murine gene and two related sequences encoding high-mobility-group I and Y proteins. Genomics. 1992;12:503–9.

    Article  CAS  PubMed  Google Scholar 

  24. Mather JF, Nathans D. Mulrivalent DNA-binding properties of the HMG-1 proteins. Proc Natl Acad Sci USA. 1996;93:6716–20.

    Article  Google Scholar 

  25. Grosschedl R, Giese K, Pagel J. HMG domain proteins: architectural elements in the assembly of nucleoprotein structures. Trends Genet. 1994;10:94–100.

    Article  CAS  PubMed  Google Scholar 

  26. Chiappetta G, Avantaggiato V, Visconti R, et al. High level expression of the HMGI (Y) gene during embryonic development. Oncogene. 1996;13:2439–6.

    CAS  PubMed  Google Scholar 

  27. Czyz W, Balcerczak E, Jakubiak M, et al. HMGI(Y) gene expression as a potential marker of thyroid follicular carcinoma. Langenbecks Arch Surg. 2004;389:193–7.

    Article  CAS  PubMed  Google Scholar 

  28. Tamimi Y, van der Poel HG, Denyn MM, et al. Increased expression of high mobility group protein I(Y) in high grade prostatic cancer determined by in situ hybridization. Cancer Res. 1993;53:5512–6.

    CAS  PubMed  Google Scholar 

  29. Fedele M, Bandiera A, Chiappetta G, et al. Human colorectal carcinomas express high levels of high mobility group HMGI(Y) proteins. Cancer Res. 1996;56:1896–901.

    CAS  PubMed  Google Scholar 

  30. Nam ES, Kim DH, Cho SJ, et al. Expression of HMGI(Y) associated with malignant phenotype of human gastric tissue. Histopathology. 2003;42:466–71.

    Article  CAS  PubMed  Google Scholar 

  31. Abe N, Watanabe T, Masaki T, et al. Pancreatic duct cell carcinomas express high levels of high mobility group I(Y) proteins. Cancer Res. 2000;60:3117–22.

    CAS  PubMed  Google Scholar 

  32. Rho YS, Lim YC, Park IS, et al. High mobility group HMGI(Y) protein expression in head and neck squamous cell carcinoma. Acta Otolaryngol. 2007;127:76–81.

    Article  CAS  PubMed  Google Scholar 

  33. Chen X, Lechago J, Ertan A, et al. Expression of the high mobility group protein HMGI(Y) correlates with malignant progression in Barrett’s metaplasia. Cancer Epidemiol Biomarkers Prev. 2004;13:30–3.

    Article  PubMed  Google Scholar 

  34. Di Cello F, Shin J, Harborm K, et al. Knockdown of HMGA1 inhibits human breast cancer cell growth and metastasis in immunodeficient mice. Biochem Biophys Res Commun. 2013;434:70–4.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Dolde CE, Mukherjee M, Cho C, et al. HMG-I/Y in human breast cancer cell lines. Breast Cancer Res Treat. 2002;71:181–91.

    Article  CAS  PubMed  Google Scholar 

  36. Belton A, Gabrovsky A, Bae YK, et al. HMGA1 induces intestinal polyposis in transgenic mice and drives tumor progression and stem cell properties in colon cancer cells. PLoS One. 2012;7:e30034.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The authors received no funding support for this study.

Disclosure

Takeshi Toyozumi, Isamu Hoshino, Masahiko Takahashi, Akihiro Usui, Yasunori Akutsu, Naoyuki Hanari, Kentaro Murakami, Masayuki Kano, Naoki Akanuma, Hiroshi Suitoh, Yasunori Matsumoto, Nobuhumi Sekino, Aki Komatsu, and Hisahiro Matsubara have no disclosures to declare.

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Authors and Affiliations

  1. Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

    Takeshi Toyozumi MD, PhD, Isamu Hoshino MD, PhD, Masahiko Takahashi MD, Akihiro Usui MD, PhD, Yasunori Akutsu MD, PhD, Naoyuki Hanari MD, PhD, Kentaro Murakami MD, PhD, Masayuki Kano MD, PhD, Naoki Akanuma MD, PhD, Hiroshi Suitoh MD, Yasunori Matsumoto MD, Nobuhumi Sekino MD, Aki Komatsu PhD & Hisahiro Matsubara MD, PhD

Authors
  1. Takeshi Toyozumi MD, PhD
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  2. Isamu Hoshino MD, PhD
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  3. Masahiko Takahashi MD
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  4. Akihiro Usui MD, PhD
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  5. Yasunori Akutsu MD, PhD
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  7. Kentaro Murakami MD, PhD
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  8. Masayuki Kano MD, PhD
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  9. Naoki Akanuma MD, PhD
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  14. Hisahiro Matsubara MD, PhD
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Corresponding author

Correspondence to Isamu Hoshino MD, PhD.

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Toyozumi, T., Hoshino, I., Takahashi, M. et al. Fra-1 Regulates the Expression of HMGA1, Which is Associated with a Poor Prognosis in Human Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 24, 3446–3455 (2017). https://doi.org/10.1245/s10434-016-5666-5

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  • DOI: https://doi.org/10.1245/s10434-016-5666-5

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