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Overexpression of HOXC11 homeobox gene in clear cell renal cell carcinoma induces cellular proliferation and is associated with poor prognosis

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Tumor Biology

Abstract

Novel evidence has confirmed the involvement of dysregulated expression of HOX genes in cancer. HOX genes are a family of 39 transcription factors, divided in four clusters (HOXA to HOXD), that during normal development regulate cell proliferation and specific cell fate. The aim of this study was to investigate whether genes of the HOXC cluster might play a role in renal cancer. The expression of HOXC11 was detected through polymerase chain reaction and immunohistochemical staining, and we demonstrated that HOXC11 was significantly higher in renal cell carcinoma (RCC) compared to normal kidney tissue. We further demonstrated that HOXC11 overexpression in HK-2 human epithelial cell line promoted proliferation, whereas downregulation of HOXC11 endogenous levels in human RCC cells (Caki-2 cells) decreased proliferation. In RCC, expression of HOXC11 and Ki67, a marker of proliferation, correlates strongly with each other (r s  = 0.47, p < 0.003). High immunohistochemical expression of HOXC11 was correlated with T stage (p = 0.06), N stage (p = 0.07), disease stage (p = 0.08), and Ki67 expression (p = 0.07), and patients with tumors showing high number of HOXC11-positive cells had shorter overall survival (p = 0.08) and shorter progression-free survival after treatment (p = 0.08) compared with patients with tumors exhibiting low amount of HOXC11-positive cells. Our data suggest that HOXC11 may contribute to RCC carcinogenesis by increasing tumor cell proliferation and imply that HOXC11 may be an important determinant of RCC patient prognosis.

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References

  1. Miyamoto H, Miller JS, Fajardo DA, Lee TK, Netto GJ, Epstein JI, et al. Non-invasive papillary urothelial neoplasms: the 2004 WHO/ISUP classification system. Pathol Int. 2010;60:1–8.

    Article  PubMed  Google Scholar 

  2. Montironi R, Santinelli A, Pomante R, Mazzucchelli R, Colanzi P, Filho AL, et al. Morphometric index of adult renal cell carcinoma. Comparison with the Fuhrman grading system. Virchows Arch. 2000;437(1):82–9.

    Article  CAS  PubMed  Google Scholar 

  3. Robinson CM, Ohh M. The multifaceted von Hippel-Lindau tumour suppressor protein. FEBS Lett. 2014;588(16):2704–11.

    Article  CAS  PubMed  Google Scholar 

  4. Keefe SM, Nathanson KL, Rathmell WK. The molecular biology of renal cell carcinoma. Semin Oncol. 2013;40(4):421–8.

    Article  CAS  PubMed  Google Scholar 

  5. Philippidou P, Dasen JS. Hox genes: choreographers in neural development, architects of circuit organization. Neuron. 2013;80(1):12–34.

    Article  CAS  PubMed  Google Scholar 

  6. Del Bene F, Wittbrodt J. Cell cycle control by homeobox genes in development and disease. Semin Cell Dev Biol. 2005;16(3):449–60.

    Article  PubMed  Google Scholar 

  7. Chen H, Sukumar S. Role of homeobox genes in normal mammary gland development and breast tumorigenesis. J Mammary Gland Biol Neoplasia. 2003;8(2):159–75.

    Article  PubMed  Google Scholar 

  8. Samuel S, Naora H. Homeobox gene expression in cancer: insights from developmental regulation and deregulation. Eur J Cancer. 2005;41(16):2428–37.

    Article  CAS  PubMed  Google Scholar 

  9. Abate-Shen C. Deregulated homeobox gene expression in cancer: cause or consequence. Nat Rev Cancer. 2002;2(10):777–85.

    Article  CAS  PubMed  Google Scholar 

  10. Chen H, Sukumar S. HOX genes: emerging stars in cancer. Cancer Biol Ther. 2003;2(10):524–5.

    Article  PubMed  Google Scholar 

  11. Maeda K, Hamada J, Takahashi Y, Tada M, Yamamoto Y, Sugihara T, et al. Altered expressions of HOX genes in human cutaneous malignant melanoma. Int J Cancer. 2005;114(3):436–41.

    Article  CAS  PubMed  Google Scholar 

  12. Alharbi RA, Pettengell R, Pandha HS, Morgan R. The role of HOX genes in normal hematopoiesis and acute leukemia. Leukemia. 2013;27(5):1000–8.

    Article  CAS  PubMed  Google Scholar 

  13. Javed S, Langley SE. Importance of HOX genes in normal prostate gland formation, prostate cancer development and its early detection. BJU Int. 2014;113(4):535–40.

    Article  CAS  PubMed  Google Scholar 

  14. Cantile M, Franco R, Schiavo G, Procino A, Cindolo L, Botti G, et al. The HOX genes network in uro-genital cancers: mechanisms and potential therapeutic implications. Curr Med Chem. 2011;18(32):4872–84.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang X, Hamada J, Nishimoto A, Takahashi Y, Murai T, Tada M, et al. HOXC6 and HOXC11 increase transcription of S100beta gene in BrdU-induced in vitro differentiation of GOTO neuroblastoma cells into Schwannian cells. J Cell Mol Med. 2007;11(2):299–306.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. McIlroy M, McCartan D, Early S, Gaora OP, Pennington S, Hill AD, et al. Interaction of developmental transcription factor HOXC11 with steroid receptor coactivator SRC-1 mediates resistance to endocrine therapy in breast cancer. Cancer Res. 2010;70(4):1585–94.

    Article  CAS  PubMed  Google Scholar 

  17. Akbas GE, Taylor HS. HOXC and HOXD gene expression in human endometrium: lack of redundancy with HOXA paralogs. Biol Reprod. 2004;70(1):39–45.

    Article  CAS  PubMed  Google Scholar 

  18. Ficarra V, Galfano A, Mancini M, Martignoni G, Artibani W. TNM staging system for renal-cell carcinoma: current status and future perspectives. Lancet Oncol. 2007;8(6):554–8.

    Article  PubMed  Google Scholar 

  19. Bitu CC, Destro MF, Carrera M, da Silva SD, Graner E, Kowalski LP, et al. HOXA1 is overexpressed in oral squamous cell carcinomas and its expression is correlated with poor prognosis. BMC Cancer. 2012;12:146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gehring WJ, Kloter U, Suga H. Evolution of the Hox gene complex from an evolutionary ground state. Curr Top Dev Biol. 2009;88:35–61.

    Article  CAS  PubMed  Google Scholar 

  21. Mallo M, Vinagre T, Carapuço M. The road to the vertebral formula. Int J DevBiol. 2009;53(8–10):1469–81.

    CAS  Google Scholar 

  22. Kongsuwan K, Webb E, Housiaux P, Adams JM. Expression of multiple homeobox genes within diverse mammalian haemopoietic lineages. EMBO J. 1988;7(7):2131–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Christensen KL, Patrick AN, McCoy EL, Ford HL. The six family of homeobox genes in development and cancer. Adv Cancer Res. 2008;101:93–126.

    Article  CAS  PubMed  Google Scholar 

  24. Jin K, Sukumar S. BRCA1: linking HOX to breast cancer suppression. Breast Cancer Res. 2010;12(4):306.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tripathi P, Guo Q, Wang Y, Coussens M, Liapis H, Jain S, et al. Midline signaling regulates kidney positioning but not nephrogenesis through Shh. Dev Biol. 2010;340(2):518–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Saxèn L. Organogenesis of the kidney. Cambridge: Cambridge Univ. Press; 1987. p. 1–173.

    Book  Google Scholar 

  27. Wu MY, Eldin KW, Beaudet AL. Identification of chromatin remodeling genes Arid4a and Arid4b as leukemia suppressor genes. J Natl Cancer Inst. 2008;100(17):1247–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Hur H, Lee JY, Yun HJ, Park BW, Kim MH. Analysis of HOX gene expression patterns in human breast cancer. Mol Biotechnol. 2014;56(1):64–71.

    Article  CAS  PubMed  Google Scholar 

  29. Walsh CA, Bolger JC, Byrne C, Cocchiglia S, Hao Y, Fagan A, et al. Global gene repression by the steroid receptor coactivator SRC-1 promotes oncogenesis. Cancer Res. 2014;74(9):2533–44.

    Article  CAS  PubMed  Google Scholar 

  30. Woo CJ, Kharchenko PV, Daheron L, Park PJ, Kingston RE. A region of the human HOXD cluster that confers polycomb-group responsiveness. Cell. 2010;140(1):99–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

Special thanks to the faculty of Department of Pathology, Zhongshan Hospital, Fudan University.

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Authors and Affiliations

  1. Department of Urology, Zhongshan Hospital, Fudan University, No. 180 Fenglin Road, Shanghai, 200032, China

    Yu-Jun Liu, Yu Zhu, Jian-Ping Zhang, Jian-Ming Guo & Zong-Ming Lin

  2. Department of Ultrasound, Zhongshan Hospital, Fudan University, Shanghai, 200032, China

    Hai-Xia Yuan

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  1. Yu-Jun Liu
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  2. Yu Zhu
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  3. Hai-Xia Yuan
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  4. Jian-Ping Zhang
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Corresponding authors

Correspondence to Jian-Ping Zhang or Jian-Ming Guo.

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Yu-Jun Liu and Yu Zhu contributed equally to this work.

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Liu, YJ., Zhu, Y., Yuan, HX. et al. Overexpression of HOXC11 homeobox gene in clear cell renal cell carcinoma induces cellular proliferation and is associated with poor prognosis. Tumor Biol. 36, 2821–2829 (2015). https://doi.org/10.1007/s13277-014-2909-6

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  • DOI: https://doi.org/10.1007/s13277-014-2909-6

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