Advertisement

Journal of Molecular Medicine

, Volume 92, Issue 8, pp 811–823 | Cite as

HOX genes and their role in the development of human cancers

  • Seema Bhatlekar
  • Jeremy Z. Fields
  • Bruce M. BomanEmail author
Review

Abstract

In this review, we summarize published findings on the involvement of HOX genes in oncogenesis. HOX genes are developmental genes—they code for proteins that function as critical master regulatory transcription factors during embryogenesis. Many reports have shown that the protein products of HOX genes also play key roles in the development of cancers. Based on our review of the literature, we found that the expression of HOX genes is not only up- or downregulated in most solid tumors but also that the expression of specific HOX genes in cancers tends to differ based on tissue type and tumor site. It was also observed that HOXC family gene expression is upregulated in most solid tumor types, including colon, lung, and prostate cancer. The two HOX genes that were reported to be most commonly altered in solid tumors were HOXA9 and HOXB13. HOXA were often reported to have altered expression in breast and ovarian cancers, HOXB genes in colon cancers, HOXC genes in prostate and lung cancers, and HOXD genes in colon and breast cancers. It was found that HOX genes are also regulated at the nuclear–cytoplasmic transport level in carcinomas. Tumors arising from tissue having similar embryonic origin (endodermal), including colon, prostate, and lung, showed relatively similar HOXA and HOXB family gene expression patterns compared to breast tumors arising from mammary tissue, which originates from the ectoderm. The differential expression of HOX genes in various solid tumors thus provides an opportunity to advance our understanding of cancer development and to develop new therapeutic agents.

Keywords

HOX genes Cancer stem cells Cancer Transcription factors Solid tumors 

Notes

Conflict of interest

None.

References

  1. 1.
    Gehring WJ, Hiromi Y (1986) Homeotic genes and the homeobox. Annu Rev Genet 20:147–173PubMedCrossRefGoogle Scholar
  2. 2.
    Lewis EB (1978) A gene complex controlling segmentation in Drosophila. Nature 276(5688):565–570PubMedCrossRefGoogle Scholar
  3. 3.
    Bridges CB (1921) Genetical and cytological proof of non-disjunction of the fourth chromosome of Drosophila melanogaster. Proc Natl Acad Sci U S A 7(7):186–192PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Nourse J et al (1990) Chromosomal translocation t(1;19) results in synthesis of a homeobox fusion mRNA that codes for a potential chimeric transcription factor. Cell 60(4):535–545PubMedCrossRefGoogle Scholar
  5. 5.
    Kamps MP et al (1990) A new homeobox gene contributes the DNA binding domain of the t(1;19) translocation protein in pre-B ALL. Cell 60(4):547–555PubMedCrossRefGoogle Scholar
  6. 6.
    Billeter M et al (1990) Determination of the three-dimensional structure of the Antennapedia homeodomain from Drosophila in solution by 1H nuclear magnetic resonance spectroscopy. J Mol Biol 214(1):183–197PubMedCrossRefGoogle Scholar
  7. 7.
    Qian YQ et al (1989) The structure of the Antennapedia homeodomain determined by NMR spectroscopy in solution: comparison with prokaryotic repressors. Cell 59(3):573–580PubMedCrossRefGoogle Scholar
  8. 8.
    Scott MP (1992) Vertebrate homeobox gene nomenclature. Cell 71(4):551–553PubMedCrossRefGoogle Scholar
  9. 9.
    Kanai M et al (2010) Aberrant expressions of HOX genes in colorectal and hepatocellular carcinomas. Oncol Rep 23(3):843–851PubMedGoogle Scholar
  10. 10.
    Freschi G et al (2005) Expression of HOX homeobox genes in the adult human colonic mucosa (and colorectal cancer?). Int J Mol Med 16(4):581–587PubMedGoogle Scholar
  11. 11.
    Vider BZ et al (2000) Deregulated expression of homeobox-containing genes, HOXB6, B8, C8, C9, and Cdx-1, in human colon cancer cell lines. Biochem Biophys Res Commun 272(2):513–518PubMedCrossRefGoogle Scholar
  12. 12.
    Vider BZ et al (1997) Human colorectal carcinogenesis is associated with deregulation of homeobox gene expression. Biochem Biophys Res Commun 232(3):742–748PubMedCrossRefGoogle Scholar
  13. 13.
    Liao WT et al (2011) HOXB7 as a prognostic factor and mediator of colorectal cancer progression. Clin Cancer Res 17(11):3569–3578PubMedCrossRefGoogle Scholar
  14. 14.
    Sanz-Pamplona R et al (2011) Gene expression differences between colon and rectum tumors. Clin Cancer Res 17(23):7303–7312PubMedCentralPubMedCrossRefGoogle Scholar
  15. 15.
    Cantile M et al (2003) In vivo expression of the whole HOX gene network in human breast cancer. Eur J Cancer 39(2):257–264PubMedCrossRefGoogle Scholar
  16. 16.
    Hur H et al (2014) Analysis of HOX gene expression patterns in human breast cancer. Mol Biotechnol 56(1):64–71PubMedCrossRefGoogle Scholar
  17. 17.
    Makiyama K et al (2005) Aberrant expression of HOX genes in human invasive breast carcinoma. Oncol Rep 13(4):673–679PubMedGoogle Scholar
  18. 18.
    Chen H, Chung S, Sukumar S (2004) HOXA5-induced apoptosis in breast cancer cells is mediated by caspases 2 and 8. Mol Cell Biol 24(2):924–935PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Raman V et al (2000) HOXA5 regulates expression of the progesterone receptor. J Biol Chem 275(34):26551–26555PubMedCrossRefGoogle Scholar
  20. 20.
    Chen H et al (2007) HOXA5 acts directly downstream of retinoic acid receptor beta and contributes to retinoic acid-induced apoptosis and growth inhibition. Cancer Res 67(17):8007–8013PubMedCrossRefGoogle Scholar
  21. 21.
    Morgan R et al (2012) Targeting the HOX/PBX dimer in breast cancer. Breast Cancer Res Treat 136(2):389–398PubMedCrossRefGoogle Scholar
  22. 22.
    Shaoqiang C et al (2013) Expression of HOXD3 correlates with shorter survival in patients with invasive breast cancer. Clin Exp Metastasis 30(2):155–163PubMedCrossRefGoogle Scholar
  23. 23.
    Shah N et al (2013) HOXB13 mediates tamoxifen resistance and invasiveness in human breast cancer by suppressing ERalpha and inducing IL-6 expression. Cancer Res 73(17):5449–5458PubMedCentralPubMedCrossRefGoogle Scholar
  24. 24.
    Ma XJ et al (2004) A two-gene expression ratio predicts clinical outcome in breast cancer patients treated with tamoxifen. Cancer Cell 5(6):607–616PubMedCrossRefGoogle Scholar
  25. 25.
    Miller GJ et al (2003) Aberrant HOXC expression accompanies the malignant phenotype in human prostate. Cancer Res 63(18):5879–5888PubMedGoogle Scholar
  26. 26.
    Waltregny D et al (2002) Overexpression of the homeobox gene HOXC8 in human prostate cancer correlates with loss of tumor differentiation. Prostate 50(3):162–169PubMedCrossRefGoogle Scholar
  27. 27.
    Axlund SD, Lambert JR, Nordeen SK (2010) HOXC8 inhibits androgen receptor signaling in human prostate cancer cells by inhibiting SRC-3 recruitment to direct androgen target genes. Mol Cancer Res 8(12):1643–1655PubMedCrossRefGoogle Scholar
  28. 28.
    Kim SD et al (2010) HOXB13 is co-localized with androgen receptor to suppress androgen-stimulated prostate-specific antigen expression. Anat Cell Biol 43(4):284–293PubMedCentralPubMedCrossRefGoogle Scholar
  29. 29.
    Ramachandran S et al (2005) Loss of HOXC6 expression induces apoptosis in prostate cancer cells. Oncogene 24(1):188–198PubMedCrossRefGoogle Scholar
  30. 30.
    Chen J et al (2013) HoxB3 promotes prostate cancer cell progression by transactivating CDCA3. Cancer Lett 330(2):217–224PubMedCrossRefGoogle Scholar
  31. 31.
    Chen JL et al (2012) Deregulation of a Hox protein regulatory network spanning prostate cancer initiation and progression. Clin Cancer Res 18(16):4291–4302PubMedCentralPubMedCrossRefGoogle Scholar
  32. 32.
    Huang Q et al (2014) A prostate cancer susceptibility allele at 6q22 increases RFX6 expression by modulating HOXB13 chromatin binding. Nat Genet 46(2):126–135PubMedCrossRefGoogle Scholar
  33. 33.
    Javed S and Langley SE (2013) Importance of HOX genes in normal prostate gland formation, prostate cancer development and its early detection. BJU IntGoogle Scholar
  34. 34.
    Cantile M et al (2005) cAMP induced modifications of HOX D gene expression in prostate cells allow the identification of a chromosomal area involved in vivo with neuroendocrine differentiation of human advanced prostate cancers. J Cell Physiol 205(2):202–210PubMedCrossRefGoogle Scholar
  35. 35.
    Omatu T (1999) [Overexpression of human homeobox gene in lung cancer A549 cells results in enhanced motile and invasive properties]. Hokkaido Igaky Zasshi 74(5):367–376Google Scholar
  36. 36.
    Abe M et al (2006) Disordered expression of HOX genes in human non-small cell lung cancer. Oncol Rep 15(4):797–802PubMedGoogle Scholar
  37. 37.
    Plowright L et al (2009) HOX transcription factors are potential therapeutic targets in non-small-cell lung cancer (targeting HOX genes in lung cancer). Br J Cancer 100(3):470–475PubMedCentralPubMedCrossRefGoogle Scholar
  38. 38.
    Bodey B et al (2000) Immunocytochemical detection of homeobox B3, B4, and C6 gene product expression in lung carcinomas. Anticancer Res 20(4):2711–2716PubMedGoogle Scholar
  39. 39.
    Costa BM et al (2010) Reversing HOXA9 oncogene activation by PI3K inhibition: epigenetic mechanism and prognostic significance in human glioblastoma. Cancer Res 70(2):453–462PubMedCentralPubMedCrossRefGoogle Scholar
  40. 40.
    Murat A et al (2008) Stem cell-related “self-renewal” signature and high epidermal growth factor receptor expression associated with resistance to concomitant chemoradiotherapy in glioblastoma. J Clin Oncol 26(18):3015–3024PubMedCrossRefGoogle Scholar
  41. 41.
    Gaspar N et al (2010) MGMT-independent temozolomide resistance in pediatric glioblastoma cells associated with a PI3-kinase-mediated HOX/stem cell gene signature. Cancer Res 70(22):9243–9252PubMedCentralPubMedCrossRefGoogle Scholar
  42. 42.
    Gallo M et al (2013) A tumorigenic MLL-homeobox network in human glioblastoma stem cells. Cancer Res 73(1):417–427PubMedCrossRefGoogle Scholar
  43. 43.
    Tabuse M et al (2011) Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells. Mol Cancer 10:60PubMedCentralPubMedCrossRefGoogle Scholar
  44. 44.
    Cantile M et al (2013) Aberrant expression of posterior HOX genes in well differentiated histotypes of thyroid cancers. Int J Mol Sci 14(11):21727–21740PubMedCentralPubMedCrossRefGoogle Scholar
  45. 45.
    Takahashi Y et al (2004) Expression profiles of 39 HOX genes in normal human adult organs and anaplastic thyroid cancer cell lines by quantitative real-time RT-PCR system. Exp Cell Res 293(1):144–153PubMedCrossRefGoogle Scholar
  46. 46.
    Gendronneau G et al (2012) The loss of Hoxa5 function causes estrous acyclicity and ovarian epithelial inclusion cysts. Endocrinology 153(3):1484–1497PubMedCentralPubMedCrossRefGoogle Scholar
  47. 47.
    Cheng W et al (2005) Lineage infidelity of epithelial ovarian cancers is controlled by HOX genes that specify regional identity in the reproductive tract. Nat Med 11(5):531–537PubMedCrossRefGoogle Scholar
  48. 48.
    Naora H et al (2001) Aberrant expression of homeobox gene HOXA7 is associated with mullerian-like differentiation of epithelial ovarian tumors and the generation of a specific autologous antibody response. Proc Natl Acad Sci U S A 98(26):15209–15214PubMedCentralPubMedCrossRefGoogle Scholar
  49. 49.
    Yamashita T et al (2006) Suppression of invasive characteristics by antisense introduction of overexpressed HOX genes in ovarian cancer cells. Int J Oncol 28(4):931–938PubMedGoogle Scholar
  50. 50.
    Ota T et al (2009) Expression and function of HOXA genes in normal and neoplastic ovarian epithelial cells. Differentiation 77(2):162–171PubMedCrossRefGoogle Scholar
  51. 51.
    Klausen C, Leung PC, Auersperg N (2009) Cell motility and spreading are suppressed by HOXA4 in ovarian cancer cells: possible involvement of beta1 integrin. Mol Cancer Res 7(9):1425–1437PubMedCrossRefGoogle Scholar
  52. 52.
    Davidson B et al (2011) Gene expression signatures differentiate ovarian/peritoneal serous carcinoma from breast carcinoma in effusions. J Cell Mol Med 15(3):535–544PubMedCrossRefGoogle Scholar
  53. 53.
    Cantile M et al (2003) Hyperexpression of locus C genes in the HOX network is strongly associated in vivo with human bladder transitional cell carcinomas. Oncogene 22(41):6462–6468PubMedCrossRefGoogle Scholar
  54. 54.
    Marra L et al (2013) Deregulation of HOX B13 expression in urinary bladder cancer progression. Curr Med Chem 20(6):833–839PubMedGoogle Scholar
  55. 55.
    Kim YJ et al (2013) HOXA9, ISL1 and ALDH1A3 methylation patterns as prognostic markers for nonmuscle invasive bladder cancer: array-based DNA methylation and expression profiling. Int J Cancer 133(5):1135–1142PubMedCrossRefGoogle Scholar
  56. 56.
    Cantile M et al (2011) Expression of lumbosacral HOX genes, crucial in kidney organogenesis, is systematically deregulated in clear cell kidney cancers. Anticancer Drugs 22(5):392–401PubMedCrossRefGoogle Scholar
  57. 57.
    Cantile M et al (2012) Increased HOX C13 expression in metastatic melanoma progression. J Transl Med 10:91PubMedCentralPubMedCrossRefGoogle Scholar
  58. 58.
    Yekta S, Tabin CJ, Bartel DP (2008) MicroRNAs in the Hox network: an apparent link to posterior prevalence. Nat Rev Genet 9(10):789–796PubMedCentralPubMedCrossRefGoogle Scholar
  59. 59.
    Niinuma T et al (2012) Upregulation of miR-196a and HOTAIR drive malignant character in gastrointestinal stromal tumors. Cancer Res 72(5):1126–1136PubMedCrossRefGoogle Scholar
  60. 60.
    Nakayama I et al (2013) Loss of HOXD10 expression induced by upregulation of miR-10b accelerates the migration and invasion activities of ovarian cancer cells. Int J Oncol 43(1):63–71PubMedGoogle Scholar
  61. 61.
    Li Q, Zhu F, Chen P (2012) miR-7 and miR-218 epigenetically control tumor suppressor genes RASSF1A and Claudin-6 by targeting HoxB3 in breast cancer. Biochem Biophys Res Commun 424(1):28–33PubMedCrossRefGoogle Scholar
  62. 62.
    Sun L et al (2011) MicroRNA-10b induces glioma cell invasion by modulating MMP-14 and uPAR expression via HOXD10. Brain Res 1389:9–18PubMedCrossRefGoogle Scholar
  63. 63.
    Mueller DW, Bosserhoff AK (2011) MicroRNA miR-196a controls melanoma-associated genes by regulating HOX-C8 expression. Int J Cancer 129(5):1064–1074PubMedCrossRefGoogle Scholar
  64. 64.
    Severino P et al (2013) MicroRNA expression profile in head and neck cancer: HOX-cluster embedded microRNA-196a and microRNA-10b dysregulation implicated in cell proliferation. BMC Cancer 13:533PubMedCentralPubMedCrossRefGoogle Scholar
  65. 65.
    Zhang JX et al (2013) HOTAIR, a cell cycle-associated long noncoding RNA and a strong predictor of survival, is preferentially expressed in classical and mesenchymal glioma. Neuro Oncol 15(12):1595–1603PubMedCrossRefGoogle Scholar
  66. 66.
    Betschinger J, Knoblich JA (2004) Dare to be different: asymmetric cell division in Drosophila, C. elegans and vertebrates. Curr Biol 14(16):R674–R685PubMedCrossRefGoogle Scholar
  67. 67.
    Amsellem S et al (2003) Ex vivo expansion of human hematopoietic stem cells by direct delivery of the HOXB4 homeoprotein. Nat Med 9(11):1423–1427PubMedCrossRefGoogle Scholar
  68. 68.
    Sauvageau G et al (1995) Overexpression of HOXB4 in hematopoietic cells causes the selective expansion of more primitive populations in vitro and in vivo. Genes Dev 9(14):1753–1765PubMedCrossRefGoogle Scholar
  69. 69.
    Buske C et al (2002) Deregulated expression of HOXB4 enhances the primitive growth activity of human hematopoietic cells. Blood 100(3):862–868PubMedCrossRefGoogle Scholar
  70. 70.
    Boman BM, Wicha MS (2008) Cancer stem cells: a step toward the cure. J Clin Oncol 26(17):2795–2799PubMedCrossRefGoogle Scholar
  71. 71.
    Boman BM et al (2008) How dysregulated colonic crypt dynamics cause stem cell overpopulation and initiate colon cancer. Cancer Res 68(9):3304–3313PubMedCrossRefGoogle Scholar
  72. 72.
    Boman BM, Huang E (2008) Human colon cancer stem cells: a new paradigm in gastrointestinal oncology. J Clin Oncol 26(17):2828–2838PubMedCrossRefGoogle Scholar
  73. 73.
    Chen YC et al (2009) Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer. Biochem Biophys Res Commun 385(3):307–313PubMedCrossRefGoogle Scholar
  74. 74.
    Bhatlekar S et al (2014) Identification of a developmental gene expression signature, including HOX genes, for the normal human colonic crypt stem cell niche: overexpression of the signature parallels stem cell overpopulation during colon tumorigenesis. Stem Cells Dev 23(2):167–179PubMedCrossRefGoogle Scholar
  75. 75.
    Vinnitsky VB (1993) Oncogerminative hypothesis of tumor formation. Med Hypotheses 40(1):19–27PubMedCrossRefGoogle Scholar
  76. 76.
    Schmitt T, Ogris C, Sonnhammer EL (2014) FunCoup 3.0: database of genome-wide functional coupling networks. Nucleic Acids Res 42(Database issue):D380–D388PubMedCentralPubMedCrossRefGoogle Scholar
  77. 77.
    Magnani L et al (2011) PBX1 genomic pioneer function drives ERalpha signaling underlying progression in breast cancer. PLoS Genet 7(11):e1002368PubMedCentralPubMedCrossRefGoogle Scholar
  78. 78.
    Mo ML et al (2013) Detection of E2A-PBX1 fusion transcripts in human non-small-cell lung cancer. J Exp Clin Cancer Res 32:29PubMedCentralPubMedCrossRefGoogle Scholar
  79. 79.
    Lawrence HJ et al (1999) Frequent co-expression of the HOXA9 and MEIS1 homeobox genes in human myeloid leukemias. Leukemia 13(12):1993–1999PubMedCrossRefGoogle Scholar
  80. 80.
    Kloetzli JM et al (2001) The winged helix gene, Foxb1, controls development of mammary glands and regions of the CNS that regulate the milk-ejection reflex. Genesis 29(2):60–71PubMedCrossRefGoogle Scholar
  81. 81.
    Siu MK et al (2013) Stem cell transcription factor NANOG controls cell migration and invasion via dysregulation of E-cadherin and FoxJ1 and contributes to adverse clinical outcome in ovarian cancers. Oncogene 32(30):3500–3509PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Seema Bhatlekar
    • 1
  • Jeremy Z. Fields
    • 2
  • Bruce M. Boman
    • 1
    • 3
    Email author
  1. 1.Center for Translational Cancer Research, Helen F. Graham Cancer Center and Research InstituteUniversity of DelawareNewarkUSA
  2. 2.CA*TX Inc.NewarkUSA
  3. 3.Kimmel Cancer Center, Department of Pharmacology and Experimental TherapeuticsThomas Jefferson UniversityPhiladelphiaUSA

Personalised recommendations