Tumor Biology

, Volume 37, Issue 2, pp 1641–1650 | Cite as

Upregulation of HOXB7 promotes the tumorigenesis and progression of gastric cancer and correlates with clinical characteristics

  • Jia-qin Cai
  • Xiao-wu Xu
  • Yi-Ping Mou
  • Ke Chen
  • Yu Pan
  • Di Wu
Original Article

Abstract

Several examples of aberrant homeobox gene expression have been found across a range of cancers, and it is also confirmed that homeobox genes play a critical roles in tumorigenesis and progression. Notwithstanding homeobox B7 (HOXB7) has been documented that its deregulation promotes carcinogenesis and development in gastrointestinal tract, its function in gastric cancer has not been investigated. In this study, HOXB7 expression was examined to be distinctly upregulated in gastric carcinoma GC cell lines and in the tumor relative to normal gastric tissue. High HOXB7 expression was correlated with tumor differentiation (P = 0.025) and TNM stage (P = 0.008). HOXB7 knockdown in BGC-823 and SGC-7901 resulted in decreased migration and invasion with alteration of epithelial-mesenchymal transition (EMT) proteins and influenced proliferation, apoptosis, and cell cycle. Furthermore, complementary DNA (cDNA) microarray, qPCR, and Western blotting were performed to explore potential downstream target genes of HOXB7. HOXB7 is generally overexpressed in GC, associated with patient clinical characteristics, and specifically promotes GC cell malignant biological properties through PIK3R3/AKT signaling pathways, indicating HOXB7 as a causal factor in promoting tumor progression.

Keywords

HOXB7 Homeobox genes Gastric cancer Clinical characteristics PIK3R3 PI3K/AKT pathway 

Notes

Acknowledgments

This study was supported by grants by Natural Science Foundation of Zhejiang Province (CN) [Grant No. LY15H160027].

Conflicts of interest

None

Supplementary material

13277_2015_3948_MOESM1_ESM.docx (16 kb)
Supplement Table 1 (DOCX 15 kb)

References

  1. 1.
    Shah MA, Kelsen DP. Gastric cancer: a primer on the epidemiology and biology of the disease and an overview of the medical management of advanced disease. J Natl Compr Cancer Netw. 2010;8:437–47.Google Scholar
  2. 2.
    Allum WH, Blazeby JM, Griffin SM, Cunningham D, Jankowski JA, Wong R. Guidelines for the management of oesophageal and gastric cancer. Gut. 2011;60:1449–72.CrossRefPubMedGoogle Scholar
  3. 3.
    Saka M, Morita S, Fukagawa T, Katai H. Present and future status of gastric cancer surgery. J Pn J Clin Oncol. 2011;41:307–13.CrossRefGoogle Scholar
  4. 4.
    Villanueva MT. Combination therapy: update on gastric cancer in East Asia. Nat Rev Clin Oncol. 2011;8:690.CrossRefPubMedGoogle Scholar
  5. 5.
    Wu WK, Lee CW, Cho CH, Fan D, Wu K, Yu J, et al. MicroRNA dysregulation in gastric cancer: a new player enters the game. Oncogene. 2010;29:5761–71.CrossRefPubMedGoogle Scholar
  6. 6.
    Thiel A, Ristimaki A. Gastric cancer: basic aspects. Helicobacter. 2012;17 Suppl 1:26–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Pearson JC, Lemons D, McGinnis W. Modulating Hox gene functions during animal body patterning. Nat Rev Genet. 2005;6:893–904.CrossRefPubMedGoogle Scholar
  8. 8.
    Samuel S, Naora H. Homeobox gene expression in cancer: insights from developmental regulation and deregulation. Eur J Cancer. 2005;41:2428–37.CrossRefPubMedGoogle Scholar
  9. 9.
    Krumlauf R. Hox genes in vertebrate development. Cell. 1994;78:191–201.CrossRefPubMedGoogle Scholar
  10. 10.
    Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 2010;10:361–71.CrossRefPubMedGoogle Scholar
  11. 11.
    Gu ZD, Chen XM, Zhang W, Gu J. Chen KN: [Expression of 39 HOX genes in esophageal cancer cell lines]. Zhonghua Wei Chang Wai Ke Za Zhi. 2007;10:365–7.PubMedGoogle Scholar
  12. 12.
    Abate-Shen C. Deregulated homeobox gene expression in cancer: cause or consequence? Nat Rev Cancer. 2002;2:777–85.CrossRefPubMedGoogle Scholar
  13. 13.
    Foronda D, de Navas LF, Garaulet DL, Sanchez-Herrero E. Function and specificity of Hox genes. Int J Dev Biol. 2009;53:1404–19.CrossRefPubMedGoogle Scholar
  14. 14.
    Hombria JC, Lovegrove B. Beyond homeosis—HOX function in morphogenesis and organogenesis. Differentiation. 2003;71:461–76.CrossRefPubMedGoogle Scholar
  15. 15.
    Shah N, Sukumar S. The Hox genes and their roles in oncogenesis. Nat Rev Cancer. 2010;10:361–71.CrossRefPubMedGoogle Scholar
  16. 16.
    Beck F. Homeobox genes in gut development. Gut. 2002;51:450–4.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Yu YY, Pan YS, Zhu ZG. Homeobox genes and their functions on development and neoplasm in gastrointestinal tract. Eur J Surg Oncol. 2007;33:129–32.CrossRefPubMedGoogle Scholar
  18. 18.
    Liao WT, Jiang D, Yuan J, Cui YM, Shi XW, Chen CM, et al. HOXB7 as a prognostic factor and mediator of colorectal cancer progression. Clin Cancer Res. 2011;17:3569–78.CrossRefPubMedGoogle Scholar
  19. 19.
    Wu X, Chen H, Parker B, Rubin E, Zhu T, Lee JS, et al. HOXB7, a homeodomain protein, is overexpressed in breast cancer and confers epithelial-mesenchymal transition. Cancer Res. 2006;66:9527–34.CrossRefPubMedGoogle Scholar
  20. 20.
    Storti P, Donofrio G, Colla S, Airoldi I, Bolzoni M, Agnelli L, et al. HOXB7 expression by myeloma cells regulates their pro-angiogenic properties in multiple myeloma patients. Leukemia. 2011;25:527–37.CrossRefPubMedGoogle Scholar
  21. 21.
    Bondos SE, Tan XX, Matthews KS. Physical and genetic interactions link hox function with diverse transcription factors and cell signaling proteins. Mol Cell Proteomics. 2006;5:824–34.CrossRefPubMedGoogle Scholar
  22. 22.
    Taghon T, Thys K, De Smedt M, Weerkamp F, Staal FJ, Plum J, et al. Homeobox gene expression profile in human hematopoietic multipotent stem cells and T-cell progenitors: Implications for human T-cell development. Leukemia. 2003;17:1157–63.CrossRefPubMedGoogle Scholar
  23. 23.
    Lu Z, Hardt J, Kim JJ. Global analysis of genes regulated by HOXA10 in decidualization reveals a role in cell proliferation. Mol Hum Reprod. 2008;14:357–66.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Garin E, Lemieux M, Coulombe Y, Robinson GW, Jeannotte L. Stromal Hoxa5 function controls the growth and differentiation of mammary alveolar epithelium. Dev Dyn. 2006;235:1858–71.CrossRefPubMedGoogle Scholar
  25. 25.
    Kongsuwan K, Webb E, Housiaux P, Adams JM. Expression of multiple homeobox genes within diverse mammalian haemopoietic lineages. EMBO J. 1988;7:2131–8.PubMedPubMedCentralGoogle Scholar
  26. 26.
    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;18:4872–84.CrossRefPubMedGoogle Scholar
  27. 27.
    Cillo C, Schiavo G, Cantile M, Bihl MP, Sorrentino P, Carafa V, et al. The HOX gene network in hepatocellular carcinoma. Int J Cancer. 2011;129:2577–87.CrossRefPubMedGoogle Scholar
  28. 28.
    Kanai M, Hamada J, Takada M, Asano T, Murakawa K, Takahashi Y, et al. Aberrant expressions of HOX genes in colorectal and hepatocellular carcinomas. Oncol Rep. 2010;23:843–51.PubMedGoogle Scholar
  29. 29.
    De Souza SDM, Bitu CC, Zecchin KG, Graner E, Lopes MA, Kowalski LP, et al. Overexpression of HOXB7 homeobox gene in oral cancer induces cellular proliferation and is associated with poor prognosis. Int J Oncol. 2010;36:141–9.Google Scholar
  30. 30.
    Chen H, Lee JS, Liang X, Zhang H, Zhu T, Zhang Z, et al. Hoxb7 inhibits transgenic HER-2/neu-induced mouse mammary tumor onset but promotes progression and lung metastasis. Cancer Res. 2008;68:3637–44.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Svingen T, Tonissen KF. Altered HOX gene expression in human skin and breast cancer cells. Cancer Biol Ther. 2003;2:518–23.CrossRefPubMedGoogle Scholar
  32. 32.
    Makiyama K, Hamada J, Takada M, Murakawa K, Takahashi Y, Tada M, et al. Aberrant expression of HOX genes in human invasive breast carcinoma. Oncol Rep. 2005;13:673–9.PubMedGoogle Scholar
  33. 33.
    Bitu CC, Carrera M, Lopes MA, Kowalski LP, Soares FA, Coletta RD. HOXB7 expression is a prognostic factor for oral squamous cell carcinoma. Histopathology. 2012;60:662–5.CrossRefPubMedGoogle Scholar
  34. 34.
    Yuan W, Zhang X, Xu Y, Li S, Hu Y, Wu S. Role of HOXB7 in regulation of progression and metastasis of human lung adenocarcinoma. Mol Carcinog. 2014;53:49–57.CrossRefPubMedGoogle Scholar
  35. 35.
    Nguyen KA, Arensman M, Lay AR, Rao NP, Donahue T, Li X, et al. HOXB7 promotes invasion and predicts survival in pancreatic adenocarcinoma. Cancer-Am Cancer Soc. 2013;119:529–39.Google Scholar
  36. 36.
    Care A, Felicetti F, Meccia E, Bottero L, Parenza M, Stoppacciaro A, et al. HOXB7: a key factor for tumor-associated angiogenic switch. Cancer Res. 2001;61:6532–9.PubMedGoogle Scholar
  37. 37.
    Care A, Silvani A, Meccia E, Mattia G, Stoppacciaro A, Parmiani G, et al. HOXB7 constitutively activates basic fibroblast growth factor in melanomas. Mol Cell Biol. 1996;16:4842–51.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Bhatlekar S, Fields JZ, Boman BM. HOX genes and their role in the development of human cancers. J Mol Med (Berl). 2014;92:811–23.CrossRefGoogle Scholar
  39. 39.
    Massague J. G1 cell-cycle control and cancer. Nature. 2004;432:298–306.CrossRefPubMedGoogle Scholar
  40. 40.
    Tetsu O, McCormick F. Beta-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature. 1999;398:422–6.CrossRefPubMedGoogle Scholar
  41. 41.
    Wu DM, Zhang P, Liu RY, Sang YX, Zhou C, Xu GC, et al. Phosphorylation and changes in the distribution of nucleolin promote tumor metastasis via the PI3K/Akt pathway in colorectal carcinoma. Febs Lett. 2014;588:1921–9.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Jia-qin Cai
    • 1
  • Xiao-wu Xu
    • 1
  • Yi-Ping Mou
    • 1
  • Ke Chen
    • 1
  • Yu Pan
    • 1
  • Di Wu
    • 1
  1. 1.Department of General Surgery, Sir Run Run Shaw Hospital, School of MedicineZhejiang UniversityHangzhouChina

Personalised recommendations